(AMG 479) Combined with Sorafenib, Panitumumab, Erlotinib, Or Gemcitabine in Patients with Advanced Solid Tumors

Author Manuscript Published OnlineFirst on April 17, 2012; DOI: 10.1158/1078-0432.CCR-11-3369 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

1 Safety and Pharmacokinetics of Ganitumab (AMG 479) 2 Combined With Sorafenib, Panitumumab, Erlotinib, or 3 Gemcitabine in Patients With Advanced Solid Tumors

4 Lee S. Rosen,1 Igor Puzanov,2 Greg R. Friberg,3 Emily Chan,2 Yuying C. Hwang,3 5 Hongjie Deng,3 Jill Gilbert,2 Devalingam Mahalingam,4 Ian McCaffery,3 Shaunita A. 6 Michael,2 Alain C. Mita,4 Monica M. Mita,4 Marilyn Mulay,1 Poornima Shubhakar,3 Min 7 Zhu,3 John Sarantopoulos4

8 1Premiere Oncology, Santa Monica, CA; 2Vanderbilt-Ingram Cancer Center, Vanderbilt 9 University Medical Center, Nashville, TN; 3Amgen Inc., Thousand Oaks, CA; 4Institute 10 for Drug Development, Cancer Therapy and Research Center, The University of Texas 11 Health Science Center at San Antonio, San Antonio, TX

12 Running title: Safety of Ganitumab Plus Targeted or Cytotoxic Agents

13 Keywords: Ganitumab, sorafenib, panitumumab, erlotinib, IGF1R

14 Financial support: This study was funded by Amgen Inc. Additional investigator 15 support for this study was provided by a Cancer Center 16 Support Grant (P30CA054174) from The University of Texas 17 Health Science Center at San Antonio, San Antonio, TX

18 Address correspondence to: Lee S. Rosen, MD 19 UCLA Hematology/Oncology 20 2020 Santa Monica Blvd, Suite 600 21 Santa Monica, CA 90404 22 Phone: 310-633-8400 23 Fax: 310-633-8419 24 E-mail: [email protected]

25 Clinical trial registration: ClinicalTrials.gov ID: NCT00974896

26 Word count: 4939 (limit, 5000)

27 Table/figure count: 6 (limit, 6)

Rosen et al 1

Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 17, 2012; DOI: 10.1158/1078-0432.CCR-11-3369 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 Statement of Translational Relevance

2 Ganitumab (AMG 479) is a fully human immunoglobulin G1 monoclonal antibody against

3 the insulin-like growth factor 1 receptor (IGF1R). In early stage trials, ganitumab had

4 acceptable toxicity and evidence of activity in patients with advanced solid tumors and

5 increased overall survival when combined with gemcitabine in patients with previously

6 untreated metastatic pancreatic cancer. Combinations of IGF1R inhibitors and targeted

7 or cytotoxic agents may improve treatment efficacy. We assessed the safety,

8 pharmacokinetics, and antitumor activity of ganitumab combined with the multikinase

9 inhibitor sorafenib, the fully human anti–epidermal growth factor receptor (EGFR)

10 monoclonal antibody panitumumab, the EGFR small-molecule inhibitor erlotinib, or the

11 nucleoside analogue gemcitabine. Ganitumab in combination with these agents was

12 generally well tolerated, had favorable pharmacokinetics, and resulted in partial

13 responses and tumor reductions in some patients. Ganitumab is currently under

14 investigation in combination with targeted and cytotoxic agents for the treatment of

15 several tumor types.

16 Abstract word count: 147 (limit, 150)

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1 Abstract

2 Purpose: This phase 1b dose-escalation study assessed safety, tolerability, and

3 pharmacokinetics of ganitumab, a fully human monoclonal antibody against the insulin-

4 like growth factor 1 (IGF1) receptor, combined with targeted agents or cytotoxic

5 chemotherapy in patients with advanced solid tumors.

6 Experimental Design: Patients with treatment-refractory advanced solid tumors were

7 sequentially enrolled at 2 ganitumab dose levels (6 or 12 mg/kg intravenously every 2

8 weeks [Q2W]) combined with either sorafenib 400 mg twice daily, panitumumab 6 mg/kg

9 Q2W, erlotinib 150 mg once daily, or gemcitabine 1000 mg/m2 on days 1, 8, and 15 of

10 each 4-week cycle. The primary endpoints were safety and pharmacokinetics of

11 ganitumab.

12 Results: Ganitumab up to 12 mg/kg appeared well tolerated combined with sorafenib,

13 panitumumab, erlotinib, or gemcitabine. Treatment-emergent adverse events were

14 generally mild and included fatigue, nausea, vomiting, and chills. Three patients had

15 dose-limiting toxicities: grade 3 hyperglycemia (ganitumab 6 mg/kg and panitumumab),

16 grade 4 neutropenia (ganitumab 6 mg/kg and gemcitabine), and grade 4

17 thrombocytopenia (ganitumab 12 mg/kg and erlotinib). Ganitumab- and panitumumab-

18 binding antibodies were detected in 5 and 2 patients, respectively; neutralizing

19 antibodies were not detected. The pharmacokinetics of ganitumab and each cotherapy

20 did not appear affected by coadministration. Circulating total IGF1 and IGF binding

21 protein 3 increased from baseline following treatment. Four patients (9%) had partial

22 responses.

23 Conclusions: Ganitumab up to 12 mg/kg was well tolerated, without adverse effects on

24 pharmacokinetics in combination with either sorafenib, panitumumab, erlotinib, or

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Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 gemcitabine. Ganitumab is currently under investigation in combination with some of

2 these and other agents.

3 Abstract word count: 249 (limit, 250)

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1 Introduction

2 The insulin-like growth factor 1 receptor (IGF1R) is a type 1 transmembrane tyrosine

3 kinase receptor that, with its ligands insulin-like growth factor 1 (IGF1) and 2 (IGF2),

4 regulates cell proliferation and apoptosis (1-4). The activity of IGFs is modulated by 6

5 IGF binding proteins (IGFBPs), which may affect tumor growth and IGF function (5).

6 There are several lines of evidence that implicate the IGF1R signaling axis in the

7 development of human malignancies (6). Not only have constitutive IGF1R expression,

8 IGF1R overexpression, and autocrine or paracrine signaling via IGF1R been proposed

9 as mechanisms of transformation in several tumor types (7-11), but studies using gene-

10 knockout mice have demonstrated that IGF1R is required for transformation (12, 13).

11 In early-phase clinical trials, IGF1R inhibitors have shown acceptable toxicity profiles

12 and evidence of antitumor activity (14). Several lines of evidence suggest that these

13 agents might be combined with other anticancer agents in the treatment of solid tumors.

14 Interactions between IGF1R and epidermal growth factor receptor (EGFR) have been

15 reported in different cell types, and IGF1R may induce EGFR phosphorylation via

16 autocrine or paracrine mechanisms involving EGF-like ligands (15-17). It was therefore

17 postulated that combined inhibition of IGF1R and vascular endothelial growth factor or

18 EGFR would be of therapeutic benefit. This rationale was further supported by

19 preclinical studies reporting additive or synergistic inhibition of tumor cell growth,

20 induction of apoptosis, and regression of tumor xenografts in several models when

21 small-molecule tyrosine kinase inhibitors of IGF1R were combined with either of the

22 EGFR inhibitors erlotinib or gefitinib (18-20). Similarly, combined treatment with an

23 IGF1R inhibitor and the multikinase inhibitor sorafenib was also associated with additive

24 inhibition of cholangiocarcinoma cell growth (21). Furthermore, combination treatment

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Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 with an IGF1R inhibitor and the cytotoxic chemotherapy gemcitabine was associated

2 with additive inhibition of human pancreatic tumor xenograft growth (22).

3 Ganitumab (AMG 479) is a fully human immunoglobulin G1 monoclonal antibody against

4 IGF1R that inhibits tumor cell proliferation, promotes tumor cell death, and causes

5 regression of established tumor xenografts (23, 24). In a phase 1, first-in-human study,

6 ganitumab as monotherapy had acceptable toxicity up to the maximum tested dose (20

7 mg/kg intravenously every 2 weeks [Q2W]) and showed antitumor activity in patients

8 with solid tumors (25). The objectives of this study were to assess the safety, tolerability,

9 and pharmacokinetics of ganitumab combined with the multikinase inhibitor sorafenib,

10 the fully human anti-EGFR monoclonal antibody panitumumab, the EGFR tyrosine

11 kinase inhibitor erlotinib, or the cytotoxic chemotherapy gemcitabine in patients with

12 advanced solid tumors. In a phase 2 study, which utilized the data from the present

13 study to justify the dose of ganitumab combined with gemcitabine, the combination had

14 acceptable toxicity and improved overall survival in patients with previously untreated

15 metastatic pancreatic cancer (26).

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1 Patients and Methods

2 Patients

3 Patients aged ≥18 years with pathologically or cytologically documented advanced solid

4 tumors or renal cell carcinoma (sorafenib cohorts) refractory to at least 1 line of therapy

5 or for which no standard or curative therapy was available; measurable or evaluable

6 disease per World Health Organization (WHO) guidelines; an Eastern Cooperative

7 Oncology Group performance status of ≤2; life expectancy ≥3 months; and adequate

8 hematologic, renal, and hepatic function were eligible to enroll.

9 Exclusion criteria included unresolved toxicities from prior anticancer therapy; primary or

10 metastatic central nervous system tumors (sorafenib cohorts only; controlled central

11 nervous system tumors were allowed in other cohorts); uncontrolled hypertension;

12 ascites or pleural effusion requiring treatment; abnormal pulmonary function, including

13 impaired carbon monoxide diffusion capacity (gemcitabine cohorts); magnesium below

14 the lower limit of normal (panitumumab cohorts); myocardial infarction, arterial

15 thrombosis, or venous thrombosis within the previous 6 months; clinically significant

16 hypoglycemia or hyperglycemia per investigator assessment; symptomatic congestive

17 heart failure; unstable angina; unstable cardiac arrhythmia requiring treatment; peptic

18 ulcer disease (sorafenib cohorts); major surgery within the previous 4 weeks (8 weeks

19 for the sorafenib cohorts); anticoagulation therapy (except low-dose warfarin) within the

20 previous week; active infection within the previous 2 weeks; and history of chronic

21 hepatitis. Diabetes (type 1 or 2) and existence or risk for primary hepatic tumors were

22 added as exclusion criteria after enrollment had begun.

23 Prior treatment with ganitumab or gemcitabine was not permitted. Prior treatment with

24 cetuximab, panitumumab, sorafenib, bevacizumab, or erlotinib was allowed. Patients

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1 were excluded for anticancer therapy, radiation therapy, antibody therapy, retinoid

2 therapy, hormonal therapy, or participation in clinical trials within the previous 4 weeks

3 before enrollment (within the previous 6 weeks for nitrosoureas and mitomycin C).

4 Concurrent hormone replacement therapy or gonadotropin-releasing hormone

5 modulators were allowed for prostate cancer. Concomitant medications that interfered

6 with cytochrome P450 3A metabolism were prohibited in the sorafenib and erlotinib

7 cohorts. Institutional review board approval was obtained for all study procedures. All

8 patients provided written informed consent before enrollment.

9 Study Design

10 This phase 1b open-label, dose-escalation study used a 3+3+3 design to investigate the

11 safety, tolerability, and pharmacokinetic profiles of ganitumab combined with sorafenib,

12 panitumumab, erlotinib, or gemcitabine. The primary endpoints were safety (incidence

13 of adverse events [AEs], clinically significant changes in vital signs and laboratory tests)

14 and pharmacokinetics of ganitumab. Secondary endpoints included the

15 pharmacokinetics of each cotherapy; anti-ganitumab antibody formation; tumor response

16 per WHO criteria; and volumetric tumor response by independent central assessment.

17 Exploratory biomarker analyses were performed, which included a pharmacodynamic

18 analysis of serum IGF1 and IGFBP-3, immunohistochemical analysis of phosphatase

19 and tensin homologue (PTEN) expression in archival tumors, and an analysis of somatic

20 mutations in archival tumors.

21 Treatment and Dose Escalation

22 Fourteen dose cohorts of 3 to 9 patients each were initially planned, which included 10

23 cohorts to assess 2 dose levels of ganitumab (6 or 12 mg/kg Q2W) combined with

24 bevacizumab 10 mg/kg Q2W, sorafenib 400 mg twice daily (BID), panitumumab 6 mg/kg

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1 Q2W, erlotinib 150 mg once daily (QD), or gemcitabine 1000 mg/m2 on days 1, 8, and 15

2 of each 28-day cycle. Four optional ganitumab de-escalation cohorts were to be

3 enrolled if intolerable toxicities occurred. Two planned bevacizumab cohorts were not

4 enrolled after new evidence indicated that bevacizumab might have limited activity as a

5 monotherapy in previously treated patients (27). The starting dose of 6 mg/kg and the

6 target dose of 12 mg/kg for ganitumab were based on pharmacokinetic results from a

7 preclinical tumor xenograft study and from the first-in-human study (25). Doses and

8 schedules for sorafenib, panitumumab, erlotinib, and gemcitabine were based on

9 product label information (28-31). Reduced doses of sorafenib and gemcitabine were

10 allowed depending on the toxicities observed.

11 Initially, 3 patients were enrolled in each cohort at the first ganitumab dose level. Up to 9

12 patients could be enrolled in each cohort for additional safety and pharmacokinetic data.

13 The decision to escalate to the second ganitumab dose level for each combination was

14 made by the investigators and sponsor following review of available safety, laboratory,

15 and pharmacokinetic data from a 21-day assessment period following the first dose. If 1

16 of 3 patients at the first dose level had a dose-limiting toxicity (DLT), then 3 additional

17 patients were to be enrolled at the first dose level. If no further DLTs or serious

18 ganitumab-related AEs were observed, enrollment in the second dose level could begin.

19 If 2 of 6 patients at the first dose level had a DLT or serious ganitumab-related AE, then

20 3 additional patients were to be enrolled at the first dose level (for a total of 9 patients).

21 A dose was considered toxic if ≥33% of patients experienced a DLT or serious

22 ganitumab-related AE during the 21-day assessment period; the dose was to be stopped

23 if 3 of 9 patients had a DLT.

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1 Ganitumab was administered as a 1-hour intravenous infusion on day 2 of cycle 1 and

2 on day 1 of each subsequent 2-week cycle. If 1-hour infusions were tolerated,

3 subsequent infusions could be reduced to 30 minutes. If 1-hour infusions were poorly

4 tolerated, subsequent infusions could be extended to 2 hours. Sorafenib was

5 administered BID orally beginning on day 1. Panitumumab was administered as a 1-

6 hour intravenous infusion on day 1 of each 2-week cycle. Erlotinib was administered QD

7 orally beginning on day 1. Gemcitabine was administered intravenously on days 1, 8,

8 and 15 of each 4-week cycle. Study drugs were administered until disease progression

9 or intolerable AE. Doses of study drugs could be withheld, reduced, or delayed per

10 protocol-specified rules for the occurrence of toxicities; interruptions lasting >6 weeks

11 resulted in study discontinuation. If ganitumab dosing was delayed, missed, or

12 discontinued, cotherapies were also delayed, missed, or discontinued; however,

13 ganitumab dosing was not altered as a result of altered dosing of cotherapies.

14 Dose-Limiting Toxicity and Maximum Tolerated Dose

15 A DLT in all cohorts (except for the gemcitabine and sorafenib cohorts) was defined as

16 any related grade ≥3 hematologic toxicity or nonhematologic toxicity occurring during the

17 initial 21 days of treatment with ganitumab (except for alopecia or other well-described

18 toxicity of the agents being investigated) according to National Cancer Institute Common

19 Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. A DLT in the

20 gemcitabine cohorts was defined as any related grade ≥3 nonhematologic toxicity

21 occurring during the initial 21 days of treatment of ganitumab (except for alopecia or

22 other well-described toxicities). Grade 3 anemia, neutropenia, and thrombocytopenia

23 were not considered DLTs unless the neutropenia was accompanied by fever >38.5°C,

24 the neutropenia lasted >7 days, or the thrombocytopenia was accompanied by bleeding.

25 Grade 4 anemia, neutropenia, and thrombocytopenia were considered DLTs. The

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1 maximum tolerated dose of ganitumab was defined as the highest dose level at which

2 <33% of treated patients in each arm had a DLT.

3 Study Assessments

4 Safety and Laboratory

5 All AEs occurring from enrollment until the last follow-up (30 days after the last dose)

6 were recorded by investigators and graded per NCI-CTCAE version 3.0. Clinical

7 chemistry, hematology, and urinalysis were assessed at screening, predose on days 1

8 and 8, before all subsequent ganitumab doses, and at the end-of-study visit.

9 Anti-ganitumab and Anti-panitumumab Antibodies

10 Blood samples for the assessment of anti-ganitumab antibodies were collected predose

11 on days 1 (for panitumumab) or 2 (for ganitumab); days 29, and 57; every 12 weeks

12 thereafter; and at the end-of-study visits (4 and 8 weeks after the last dose). Anti-

13 ganitumab antibodies were assayed using an electrochemiluminescence bridging

14 immunoassay as described previously (25). Anti-panitumumab antibodies were assayed

15 using a bridging enzyme-linked immunosorbent assay (ELISA) and a Biacore assay as

16 described previously (32).

17 Pharmacokinetics

18 Blood samples for the measurement of pharmacokinetic profiles of ganitumab, sorafenib,

19 panitumumab, erlotinib, and gemcitabine and its metabolite (2’2’-difluorodeoxyuridine

20 [dFdU]) were collected between weeks 5 (cycle 3, predose and postdose) and 7 (cycle 4,

21 predose). Sparse samples were collected in weeks 1 (cycle 1, predose and postdose), 3

22 (cycle 2, predose and postdose), 11 (cycle 6, predose), and 15 (cycle 8, predose);

23 predose every 12 weeks thereafter; and at the end-of-study visits (4 and 8 weeks after

24 the last dose). Serum concentrations of ganitumab and panitumumab were measured

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1 using a double anti-idiotypic antibody sandwich immunoassay (25) and an

2 electrochemiluminescence assay (33), respectively. Plasma concentrations of sorafenib,

3 erlotinib, gemcitabine, and dFdU were measured by liquid chromatography with tandem

4 mass spectrometry (see Supplemental Material). Pharmacokinetic parameters were

5 estimated using noncompartmental methods with WinNonlin® software (version 5.1.1;

6 Pharsight Corp., Mountain View, CA).

7 Pharmacodynamic Assessments

8 To assess the pharmacodynamic response of circulating IGF1 and IGFBP-3 to treatment

9 with ganitumab, blood samples for the measurement of serum total IGF1 and IGFBP-3

10 were collected predose in cycles 1 (days 1, 2, and 8), 2 (day 15), 4 (day 43), and 6 (day

11 71) and at the end-of-study visit (4 weeks after the last dose of ganitumab). Serum IGF1

12 and IGFBP-3 were measured using competitive binding radioimmunoassays following

13 alcohol/acid extraction. Briefly, extracts were incubated with rabbit polyclonal antisera

14 specific for IGF1 or IGFBP-3 followed by radioiodinated purified recombinant human

15 IGF1 or purified IGFBP-3. Concentrations of IGF1 and IGFBP-3 from control and test

16 samples were determined from a dose-response curve generated in each assay using

17 purified IGF1 or IGFBP-3. The sensitivities of the assays for IGF1 and IGFBP-3 were 15

18 ng/mL and 0.3 ng/mL, respectively.

19 Analysis of Tumor PTEN Expression

20 Archival tumor samples were stained for nuclear and cytoplasmic expression of

21 phosphatase and tensin homologue (PTEN) by immunohistochemistry and scored on a

22 relative scale of 0 to 3 (0 = no stain; 3 = maximal stain). Tumor cells with a staining

23 intensity ≥1 in the nuclear or cytoplasmic compartments were considered PTEN-positive.

24 Detailed staining methods are described in the Supplemental Material.

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1 Exploratory Genetic Analysis

2 DNA was extracted from archival formalin-fixed paraffin-embedded sections. To

3 determine the somatic mutation status of HRAS, KRAS, NRAS, BRAF, PIK3CA, PTEN,

4 and TP53, sequence libraries were generated and analyzed using the Roche 454 GS

5 FLX Amplicon Sequencing platform (454 Life Sciences, Branford, CT). Detailed

6 methods are available in the Supplemental Material.

7 Tumor Assessment

8 Tumor assessment was performed by computed tomography (CT) or magnetic

9 resonance imaging and was evaluated by investigators within 4 weeks before enrollment

10 and every 8 weeks (± 1 week) thereafter. Volumetric CT analysis was performed by a

11 central imaging laboratory (VirtualScopics, Rochester, NY). Response was assessed by

12 investigators per WHO criteria (34). A partial response was defined as a ≥50%

13 decrease from baseline in the sum of the cross-products of the longest diameters (SPD)

14 of index lesions for ≥4 weeks. Progressive disease was defined as at least a 25%

15 increase in the SPD of index lesions taking as reference the nadir SPD recorded since

16 the last treatment started or the presence of one or more new lesions. Stable disease

17 was defined as neither sufficient shrinkage of index lesions to qualify for a partial

18 response nor sufficient increase to qualify for progressive disease, taking as reference

19 the nadir SPD since the treatment started. For duration of responses, responders who

20 had not progressed or died during the study were censored at the last disease

21 assessment.

22 Statistical Analysis

23 Descriptive statistics were used to summarize demographic, safety, pharmacokinetic,

24 biomarker, tumor assessment, and response data. The safety-analysis set included all

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1 patients who received ≥1 dose of investigational product. All patients were included in

2 efficacy analyses. Patients were categorized by the initial dose received.

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1 Results

2 Patient Demographics and Disposition

3 Forty-six patients were enrolled at 3 centers in the United States between December 5,

4 2006 and September 2, 2009. All patients received at least 1 dose of ganitumab; 9

5 received at least 24 weeks of treatment. All patients received at least 1 dose of their

6 respective cotherapies. Administration of the study drugs is summarized in

7 Supplemental Table 1. Patients were enrolled sequentially, first completing treatment

8 in the gemcitabine and panitumumab cohorts, followed by the sorafenib and erlotinib

9 cohorts. Demographics and baseline characteristics are summarized in Table 1. The

10 most common tumor types were colon (n=11), ovarian (n=6), breast (n=4), and non–

11 small-cell lung (n=3). The majority of patients (n=31; 67%) had received ≥3 lines of prior

12 cancer therapy, and approximately one half had received radiotherapy (n=24; 52%).

13 Eleven patients (24%) discontinued the study early; reasons included consent withdrawn

14 (n=4), loss to follow-up (n=2; after 4 and 6 doses, respectively), alternative therapy (n=2),

15 noncompliance (n=1), AE (n=1) (see below, Dose-Limiting Toxicities), and administrative

16 decision (n=1). Thirty-five patients (76%) completed the end-of-study visit.

17 Dose Escalation, Dose-Limiting Toxicities, and Maximum Tolerated Dose

18 Overall, 8 cohorts were enrolled in the study, comprising 20 patients in the ganitumab 6-

19 mg/kg cohorts and 26 patients in the ganitumab 12-mg/kg cohorts. Initially, 3 patients

20 were enrolled in cohorts to receive ganitumab 6 mg/kg combined with sorafenib 400 mg

21 BID (cohort 1), panitumumab 6 mg/kg Q2W (cohort 2), erlotinib 150 mg QD (cohort 3), or

22 gemcitabine 1000 mg/m2 (cohort 4). Two of these patients had DLTs: 1 in cohort 2 and

23 1 in cohort 4. In cohort 2, a patient with a thyroid tumor and history of diabetes had

24 grade 3 hyperglycemia considered by investigators to be related to ganitumab. The

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1 patient’s baseline fasting glucose was 103 mg/dL; subsequent levels ranged from 189 to

2 350 mg/dL. The patient received treatment with insulin and the panitumumab dose was

3 altered; the patient was eventually removed from the study owing to hyperglycemia. In

4 cohort 4, a patient with a small-cell lung tumor had grade 4 neutropenia. As a result of

5 the DLTs, cohorts 2 and 4 were each expanded to 6 patients to collect additional safety

6 and pharmacokinetic data. Additionally, 2 patients were enrolled in cohort 4 as

7 replacements for 2 patients who received ganitumab dosing errors (12 mg/kg instead of

8 6 mg/kg ganitumab) during the DLT assessment window.

9 Subsequently, 3 patients were enrolled in cohorts to receive ganitumab 12 mg/kg

10 combined with sorafenib (cohort 5), panitumumab (cohort 6), erlotinib (cohort 7), or

11 gemcitabine (cohort 8). One patient in cohort 7 with ovarian cancer had a DLT (grade 4

12 thrombocytopenia) after the first dose of ganitumab (day 5). The patient was removed

13 from the study and did not receive subsequent treatment. Subsequently, cohorts 5 and

14 7 were expanded to 9 patients to collect additional safety and pharmacokinetic data.

15 Additionally, 1 patient each in cohorts 5 and 6 were replaced due to consent withdrawal

16 and failure to complete DLT window, resulting in a total enrollment of 10 and 4 patients,

17 respectively. Ganitumab at the highest tested dose of 12 mg/kg appeared to be well

18 tolerated when combined with full doses of each cotherapy (as defined by a DLT rate

19 <33%).

20 Safety and Tolerability

21 Toxicity is summarized in Table 2. The most frequent ganitumab-related AEs were

22 fatigue, nausea, vomiting, chills not associated with infusion, anorexia, and

23 thrombocytopenia. The AEs considered related to treatment with the cotherapies were

24 consistent with those previously reported for these agents (35-37). Grade ≥3 treatment-

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1 emergent AEs occurred in 33 patients (72%). The most common (occurring in ≥4% of

2 patients) grade ≥3 treatment-emergent AEs were neutropenia, fatigue, anemia, palmar-

3 plantar erythrodysesthesia syndrome, hypomagnesemia, rash, intestinal obstructions,

4 and dehydration (see Table 2). Grade ≥3 ganitumab-related AEs (each n=1) were

5 fatigue (cohort 5), thrombocytopenia (cohort 4), cataract (cohort 1), hyperglycemia

6 (cohort 2), hyponatremia (cohort 5), and neutropenia (cohort 5). Serious AEs occurred

7 in 15 patients (33%), none of which were considered by investigators to be related to

8 ganitumab. The most frequent (occurring in ≥4% of patients) serious AEs were

9 dehydration (cohort 5, n=1 [10%]; cohort 7, n=1 [11%]), diarrhea (cohort 5, n=1 [10%];

10 cohort 7, n=1 [11%]), and intestinal obstruction (cohort 3, n=1 [13%]; cohort 7, n=1;

11 [11%]). Dehydration and diarrhea were the only serious AEs considered by investigators

12 to be potentially related to treatment with a study drug (sorafenib; cohort 5).

13 Hyperglycemia was not reported in any patient aside from the occurrence considered a

14 DLT. Two patients had hepatotoxicity events (grade 2 hepatic pain and grade 3

15 increased alanine aminotransferase), neither of which was considered by investigators

16 to be related to ganitumab; however, the increased alanine aminotransferase was

17 considered by investigators to be potentially related to treatment with sorafenib. Three

18 patients (7%) had AEs identified as potential sensorineural hearing loss. However, only

19 1 patient (cohort 7) had sensorineural hearing loss (grade 2 hypoacusis) considered by

20 investigators to be potentially related to ganitumab. The patient had prior exposure to

21 loud noises and a 3- to 6-month history of diminished hearing before enrollment. No

22 infusion reactions were reported during the study.

23 AEs considered potentially related to treatment with the cotherapies were consistent with

24 those previously reported for these agents (35-37). Neutropenia events were reported in

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1 7 patients (15%) overall and occurred predominantly in the gemcitabine cohorts (cohort

2 4, n=4; cohort 5, n=1; cohort 8, n=2). In addition to the 1 case of grade 4 neutropenia in

3 cohort 4 considered a DLT, grade 3 neutropenia occurred in 5 patients (cohort 4, n=3;

4 cohort 8, n=2), grade 4 neutropenia occurred in 1 patient in cohort 5, and grade 1

5 leukopenia occurred in 1 patient in cohort 8. Of these events, only the grade 1

6 leukopenia and the grade 4 neutropenia were considered by the investigators to be

7 potentially related to ganitumab. The grade 4 neutropenia was not considered a DLT

8 because it occurred after the 21-day assessment period. Thrombocytopenia events

9 occurred in the gemcitabine cohort (n=7) and in the erlotinib cohort (n=3).

10 Skin rash occurred in 33 patients (72%) overall and in 76%, 100%, 75%, and 36% of

11 patients in the sorafenib, panitumumab, erlotinib, and gemcitabine cohorts, respectively.

12 One patient who received sorafenib (cohort 5) had a grade 3 superior vena cava

13 occlusion that was not considered related to ganitumab.

14 The only treatment discontinuations as a result of AEs are described above (cohort 2,

15 hyperglycemia; cohort 7, thrombocytopenia). Delays in and reduced dosing of

16 ganitumab occurred in 6 and 3 patients, respectively, as a result of AEs. One patient

17 (cohort 5) died on study day 61 of respiratory failure not considered by investigators to

18 be related to treatment with ganitumab. This patient, who had ovarian cancer for 10

19 years, had multiple surgeries and had been heavily pretreated with various

20 chemotherapy agents prior to enrollment.

21 Antibodies

22 Ganitumab-binding antibodies were detected in 5 patients (11%) during the study, 2 of

23 whom had detectable binding antibodies at or before baseline. Ganitumab-neutralizing

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1 antibodies were not detected in any patient before or during the study. Panitumumab-

2 binding antibodies were detected in 2 patients (1 each in cohorts 2 and 6) with the

3 Biacore assay but were not detected with the ELISA. In the patients with detectable

4 binding antibodies with the Biacore assay, none were detected at or before baseline or

5 within 90 days of the last dose. Panitumumab-neutralizing antibodies were not detected

6 in any patient during the study.

7 Pharmacokinetics

8 The pharmacokinetic parameters of ganitumab and each cotherapy are shown in Tables

9 3 and 4, respectively. Estimates of mean ganitumab exposure (maximum observed

10 serum concentration, minimum observed serum concentration, and area under the

11 concentration versus time curve for a dosing interval) were approximately 2-fold greater

12 among patients who received ganitumab 12 mg/kg versus 6 mg/kg in all cohorts,

13 indicating that dose linearity was not affected by coadministration with sorafenib,

14 panitumumab, erlotinib, or gemcitabine. Ganitumab clearance at both the 6- and 12-

15 mg/kg doses in combination with sorafenib, panitumumab, erlotinib, and gemcitabine

16 ranged from 8.94 to 17.0 mL/d/kg, which was within the expected range with

17 monotherapy (25). Estimated pharmacokinetic parameters for sorafenib, panitumumab,

18 erlotinib, and gemcitabine did not appear to be affected by coadministration with

19 ganitumab (Table 4).

20 Tumor Response

21 Overall, 39 of 46 patients had evaluations of tumor response per WHO criteria (34) per

22 investigator assessment. Of these, 35 had both baseline and post-treatment imaging; 4

23 had assessments based on new lesions or non-index lesions (described in Figure 1

24 legend). The best-result changes from baseline in SPD of index lesions of 35 patients

Rosen et al 19

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 are shown in Figure 1. Four patients (9%) had partial responses as a best result. For

2 these 4 patients, the duration of objective response was: 24.0 weeks for a patient with

3 endometrial cancer in cohort 1 (sorafenib), 25.4 weeks for a patient with breast cancer in

4 cohort 3 (erlotinib; censored at last assessment), 24.1 weeks for a patient with colon

5 cancer in cohort 6 (panitumumab), and 16.9 weeks for a patient with prostate cancer in

6 cohort 8 (gemcitabine). These 4 patients were heavily pretreated, having previously

7 received multiple cytotoxic and targeted therapies. Twenty-three patients had a best

8 result of stable disease (sorafenib cohorts: cohorts 1 [n=2], cohort 5 [n=5]; panitumumab

9 cohorts: cohort 2 [n=5], cohort 6 [n=1]; erlotinib cohorts: cohort 3 [n=1], cohort 7 [n=1];

10 gemcitabine cohorts: cohort 4 [n=7], cohort 8 [n=1]). Among these, 6 received treatment

11 ≥24 weeks, and the most frequent primary tumor types were colon (n=5), thyroid, non–

12 small-cell lung, squamous cell, and ovarian (all n=2). The remaining 12 evaluable

13 patients had progressive disease as a best result (sorafenib cohorts: cohort 1 [n=0],

14 cohort 5 [n=3]; panitumumab cohorts: cohort 2 [n=1], cohort 6 [n=1]; erlotinib cohorts:

15 cohort 3 [n=1], cohort 7 [n=4]; gemcitabine cohorts: cohort 4 [n=1], cohort 8 [n=1]).

16 There were no significant discordances in tumor response between the investigator and

17 central assessments.

18 Assessment of Potential Biomarkers

19 At the 6- and 12-mg/kg doses of ganitumab, mean total serum levels of IGF1 increased

20 from baseline to day 8 and remained relatively constant through week 11 or the end of

21 study (Figure 2A). At day 15 (collected at trough levels before the second dose), the

22 IGF1 ratio to baseline was 1.31 at the 12-mg/kg dose of ganitumab and 1.20 at the 6-

23 mg/kg dose, indicating the presence of a dose-dependent pharmacodynamic effect at

24 both ganitumab dose levels. Mean total serum levels of IGFBP-3 increased from

25 baseline to the end of study at both dose levels of ganitumab (Figure 2B). No dose-

Rosen et al 20

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 dependent differences were observed. No associations were observed between the

2 pharmacodynamic markers and change from baseline in SPD of target lesions.

3 We assessed potential associations between PTEN expression and response to

4 treatment with ganitumab combined with sorafenib, panitumumab, erlotinib, and

5 gemcitabine. Although immunohistochemical analysis of archival tumor samples

6 confirmed cytoplasmic and nuclear expression of PTEN in the majority of available

7 specimens, there was no observed association between the proportion of PTEN-positive

8 cells and percentage change in SPD of target lesions (Supplemental Table 2).

9 An exploratory analysis of somatic mutations in genes with potential involvement in the

10 IGF1R and EGFR signaling pathways (KRAS, BRAF, HRAS, NRAS, PIK3CA, PTEN,

11 AKT, and TP53) did not demonstrate an association between mutation status and

12 change from baseline in SPD of target lesions. However, it is important to note that this

13 analysis, and the analysis of tumor PTEN expression, was limited by the small number

14 of samples and mixed patient population.

Rosen et al 21

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 Discussion

2 In this study, ganitumab was well tolerated up to the maximum tested dose of 12 mg/kg

3 when combined with sorafenib, panitumumab, erlotinib, or gemcitabine in patients with

4 advanced solid tumors. Three patients had DLTs (cohorts 2, 4, and 7), but when cohorts

5 were expanded, there were no further DLTs. AEs related to treatment with agents other

6 than ganitumab were consistent with those expected for each agent.

7 Grade 3 hyperglycemia was observed in a patient in cohort 2 (ganitumab 6 mg/kg

8 combined with panitumumab) who had a history of controlled diabetes. Among patients

9 in the first-in-human study who did not have diabetes (n=50), hyperglycemia occurred in

10 3 patients who received ganitumab 12 mg/kg Q2W and 2 patients who received

11 ganitumab 20 mg/kg Q2W; an additional 2 of 3 patients with diabetes had decreased

12 glucose control (25). In a randomized phase 2 study, grade 3 or 4 hyperglycemia was

13 observed in 18% of patients with metastatic pancreatic cancer who received ganitumab

14 plus gemcitabine (26). In addition, grade 1 to 4 hyperglycemia has been reported in

15 phase 1 studies of the IGF1R inhibitor figitumumab (38-40). Thrombocytopenia has

16 been previously reported among patients receiving ganitumab treatment (25, 26). In this

17 study, thrombocytopenia events and severe neutropenia occurred predominantly among

18 patients who also received erlotinib or gemcitabine, which is consistent with studies

19 assessing these agents in metastatic cancer of the pancreas (41, 42). Thus, although

20 this study was small, there was no evidence of interactions that resulted in toxicity

21 greater than expected with any of the combinations assessed.

22 The ganitumab pharmacokinetic parameters estimated in this study were generally

23 consistent with those in the monotherapy first-in-human study (25), suggesting that the

24 pharmacokinetics of ganitumab was not affected in combination with sorafenib,

Rosen et al 22

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 panitumumab, erlotinib, or gemcitabine. There is no mechanism-based pharmacokinetic

2 interaction expected when ganitumab is administered with small-molecule drugs, owing

3 to different elimination pathways, or with monoclonal antibodies, owing to the large

4 capacity in elimination of immunoglobulin G antibodies. It has been reported that

5 baseline serum albumin and creatinine levels could affect ganitumab exposure levels

6 (43), which underscores the potential influence of baseline disease status and

7 characteristics.

8 We hypothesized that combination therapy might improve patient outcomes versus

9 single-agent inhibition of the IGF1R pathway, and therefore chose to explore the

10 antitumor activity of ganitumab in a variety of combinations with cytotoxic and targeted

11 therapies. Although antitumor activity was not a primary objective of this phase 1b study

12 of heavily pretreated patients, 4 of 46 patients (9%) with the following tumor types had

13 partial responses: endometrial (cohort 1), breast (cohort 3), colon (cohort 6), and

14 prostate cancer (cohort 8). Twenty-three patients (59%) had stable disease, including 1

15 patient with neuroendocrine cancer and 1 patient with pancreatic cancer. One partial

16 response occurred in each of the sorafenib, erlotinib, panitumumab, and gemcitabine

17 cohorts with ganitumab at either dose level. Although these results suggest that there

18 was some evidence of antitumor activity for each of the combinations, larger studies will

19 be required to assess whether there were improvements in outcomes with these

20 combinations versus single-agent treatment.

21 In the pharmacodynamic biomarker analysis, serum total IGF1 and IGFBP-3 increased

22 from baseline following treatment with ganitumab at both dose levels. Similar increases

23 in circulating IGF1 were observed following treatment with ganitumab 20 mg/kg in the

24 first-in-human study (25).

Rosen et al 23

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 In an exploratory analysis, we investigated whether there was an association between

2 tumor expression of PTEN and tumor response. Preclinical evidence has suggested

3 that the IGF1 signaling pathway promotes tumor cell proliferation and invasiveness

4 through dephosphorylation of the tumor suppressor PTEN and activation of the

5 PI3K/PTEN/Akt/NF-κB signaling pathway (44). Furthermore, loss of PTEN expression

6 has been associated with poor outcomes among cancer patients (45, 46) and with lack

7 of response to anti-EGFR therapy for metastatic colorectal cancer (47). Although the

8 majority of tumor samples in the present study were assessed as PTEN-positive, there

9 was no association between PTEN expression and change in tumor dimensions in the

10 limited number of samples from a mixed patient population.

11 In conclusion, ganitumab at the target dose of 12 mg/kg combined with the approved

12 doses of sorafenib, panitumumab, erlotinib, or gemcitabine had acceptable toxicity and

13 showed evidence of antitumor activity, suggesting that further studies of ganitumab

14 combinations for the treatment of solid tumors may be warranted at the doses

15 established in this trial. Ganitumab combined with gemcitabine in metastatic pancreatic

16 cancer is currently being investigated in a randomized phase 3 study (Gemcitabine and

17 AMG 479 in Metastatic Adenocarcinoma of the Pancreas [GAMMA]; Clinicaltrials.gov,

18 NCT01231347).

Rosen et al 24

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 Acknowledgment

2 The authors would like to acknowledge Li Chen (Amgen Inc.), PhD, ScD, for

3 biostatistical analysis, Jessica Johnson (Amgen Inc.) BS, for pharmacokinetic data

4 analysis, Jennifer L. Gansert (Amgen Inc.), MD, PhD, for helpful comments, and

5 Benjamin Scott, PhD, whose work was funded by Amgen Inc., for assistance in writing

6 this manuscript.

Rosen et al 25

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

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Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. Safety of Ganitumab Plus Targeted or Cytotoxic Agents Downloaded from Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369

Tables

clincancerres.aacrjournals.org Table 1. Patient Demographics and Baseline Characteristics*

Cohort 1 Cohort 5 Cohort 2 Cohort 6 Cohort 3 Cohort 7 Cohort 4 Cohort 8 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab + + + + + + + + 400 mg BID 400 mg BID 6 mg/kg Q2W 6 mg/kg Q2W 150 mg QD 150 mg QD 1000 mg/m2 1000 mg/m2 Sorafenib Sorafenib Panitumumab Panitumumab Erlotinib Erlotinib Gemcitabine Gemcitabine Total (n=3) (n=10) (n=6) (n=4) (n=3) (n=9) (n=8) (n=3) (n=46)

Research. Women 1 (33) 5 (50) 1 (17) 2 (50) 1 (33) 7 (78) 6 (75) 2 (67) 25 (54)

Race, n (%) White/Caucasian 1 (33) 10 (100) 5 (83) 4 (100) 3 (100) 8 (89) 5 (63) 1 (33) 37 (80) Black/ African American 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 2 (67) 3 (7) Hispanic/Latino 2 (67) 0 (0) 0 (0) 0 (0) 0 (0) 1 (11) 2 (25) 0 (0) 5 (11) Asian 0 (0) 0 (0) 1 (17) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)

Median age, y (range) 65 (61–74) 51 (41–63) 56 (51–63) 55 (33–68) 63 (55–69) 59 (44–73) 58 (32–64) 70 (44–73) 57 (32–74)

ECOG performance status, n (%) 0 0 (0) 3 (30) 2 (33) 2 (50) 1 (33) 2 (22) 4 (50) 0 (0) 14 (30) 1 3 (100) 7 (70) 4 (67) 2 (50) 2 (67) 7 (78) 4 (50) 3 (100) 32 (70)

Primary tumor type, n (%) Colon 0 (0) 0 (0) 3 (50) 3 (75) 0 (0) 2 (22) 2 (25) 1 (33) 11 (24) Ovarian 0 (0) 2 (20) 0 (0) 0 (0) 0 (0) 2 (22) 2 (25) 0 (0) 6 (13) Breast 0 (0) 1 (10) 0 (0) 0 (0) 1 (33) 1 (11) 1 (13) 0 (0) 4 (9) Non–small-cell lung 0 (0) 1 (10) 0 (0) 0 (0) 1 (33) 0 (0) 1 (13) 0 (0) 3 (7) Carcinoid 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 1 (11) 0 (0) 0 (0) 2 (4) Endometrial 1 (33) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (4) Small-cell lung 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (11) 1 (13) 0 (0) 2 (4) Thyroid 1 (33) 0 (0) 1 (17) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (4) Angiosarcoma 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (11) 0 (0) 0 (0) 1 (2) Carcinoma of unknown origin 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 1 (2)

Rosen et al 33 Safety of Ganitumab Plus Targeted or Cytotoxic Agents Downloaded from Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Cohort 1 Cohort 5 Cohort 2 Cohort 6 Cohort 3 Cohort 7 Cohort 4 Cohort 8 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369 Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab + + + + + + + + 400 mg BID 400 mg BID 6 mg/kg Q2W 6 mg/kg Q2W 150 mg QD 150 mg QD 1000 mg/m2 1000 mg/m2

clincancerres.aacrjournals.org Sorafenib Sorafenib Panitumumab Panitumumab Erlotinib Erlotinib Gemcitabine Gemcitabine Total (n=3) (n=10) (n=6) (n=4) (n=3) (n=9) (n=8) (n=3) (n=46) Esophageal 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 0 (0) 0 (0) 0 (0) 1 (2) Gastroesophageal junction 0 (0) 0 (0) 1 (17) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Head and neck adenocarcinoma 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (11) 0 (0) 0 (0) 1 (2) Hepatocellular carcinoma 1 (33) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Leiomyosarcoma 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Squamous cell carcinoma of the anus 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Neuroendocrine 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Pancreatic 0 (0) 0 (0) 1 (17) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Prostate 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 1 (2) on September 27, 2021. © 2012American Association for Cancer Rectal 0 (0) 0 (0) 0 (0) 1 (25) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)

Research. Sacrum chordoma 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Squamous cell head/neck 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 0 (0) 1 (2)

Lines of prior therapy, n (%)

0 † † 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 1 (33) 2 (4) 1 0 (0) 1 (10) 1 (17) 0 (0) 0 (0) 1 (11) 0 (0) 0 (0) 3 (7) 2 0 (0) 2 (20) 3 (50) 0 (0) 0 (0) 3 (33) 2 (25) 0 (0) 10 (22) ≥3 3 (100) 7 (70) 2 (33) 4 (100) 3 (100) 5 (56) 5 (63) 2 (67) 31 (67)

Lines of prior radiotherapy, n (%)

0 1 (33) 4 (40) 1 (17) 4 (100) 0 (0) 5 (56) 5 (63) 2 (67) 22 (48) 1 0 (0) 2 (20) 4 (67) 0 (0) 2 (67) 4 (44) 0 (0) 0 (0) 12 (26) 2 1 (33) 2 (20) 1 (17) 0 (0) 0 (0) 0 (0) 2 (25) 1 (33) 7 (15) ≥3 1 (33) 2 (20) 0 (0) 0 (0) 1 (33) 0 (0) 1 (13) 0 (0) 5 (11) BID, twice daily; ECOG, Eastern Cooperative Oncology Group; Q2W, every 2 weeks; QD, once daily. *Safety analysis set includes patients who received ≥1 dose of ganitumab. †Patients were eligible if they had advanced solid tumors refractory to ≥1 line of therapy, if no standard or curative therapy was available, or if standard noncurative therapy was refused.

Rosen et al 34 Safety of Ganitumab Plus Targeted or Cytotoxic Agents Downloaded from Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited.

Table 2. Summary of Adverse Events* Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369

Cohort 1 Cohort 5 Cohort 2 Cohort 6 Cohort 3 Cohort 7 Cohort 4 Cohort 8 clincancerres.aacrjournals.org 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab + + + + + + + + 400 mg BID 400 mg BID 6 mg/kg Q2W 6 mg/kg Q2W 150 mg QD 150 mg QD 1000 mg/m2 1000 mg/m2 Sorafenib Sorafenib Panitumumab Panitumumab Erlotinib Erlotinib Gemcitabine Gemcitabine Total Patients, n (%) (n=3) (n=10) (n=6) (n=4) (n=3) (n=9) (n=8) (n=3) (n=46)

Patients with ≥1 treatment- 3 (100) 10 (100) 6 (100) 4 (100) 3 (100) 9 (100) 8 (100) 3 (100) 46 (100) emergent AE

Patients with ≥1 serious AE 1 (33) 6 (60) 1 (17) 0 (0) 2 (67) 4 (44) 1 (13) 0 (0) 15 (33)

on September 27, 2021. © 2012American Association for Cancer Patients with fatal AEs 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) Research. Patients with ganitumab-related AEs† 3 (100) 8 (80) 4 (67) 3 (75) 2 (67) 7 (78) 5 (63) 3 (100) 35 (76) Fatigue 1 (33) 3 (30) 2 (33) 1 (25) 1 (33) 1 (11) 2 (25) 0 (0) 11 (24) Nausea 1 (33) 1 (10) 1 (17) 0 (0) 0 (0) 2 (22) 2 (25) 0 (0) 7 (15) Chills 1 (33) 3 (30) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 1 (33) 6 (13) Vomiting 1 (33) 0 (0) 1 (17) 0 (0) 0 (0) 0 (0) 2 (25) 2 (67) 6 (13) Stomatitis or mucosal inflammation 0 (0) 2 (20) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 1 (33) 4 (8) Rash or maculopapular rash 0 (0) 1 (10) 0 (0) 0 (0) 1 (33) 0 (0) 1 (13) 1 (33) 4 (8) Anorexia 1 (33) 0 (0) 1 (17) 0 (0) 0 (0) 0 (0) 1 (13) 0 (0) 3 (7) Thrombocytopenia 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 1 (11) 0 (0) 1 (33) 3 (7) Alopecia 1 (33) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (4) Diarrhea 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 1 (11) 0 (0) 0 (0) 2 (4) Hypertension 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 0 (0) 2 (4) Hypomagnesemia 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 0 (0) 2 (4) Myalgia 0 (0) 2 (20) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (4) Pruritus 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 1 (33) 2 (4) Pyrexia 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 1 (13) 0 (0) 2 (4)

Patients with grade ≥3 treatment-emergent AEs† 2 (67) 10 (100) 5 (83) 3 (75) 2 (67) 4 (44) 5 (63) 2 (67) 33 (72) Neutropenia 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 4 (50) 2 (67) 7 (15) Palmar-plantar erythrodysesthesia syndrome 2 (67) 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (7) Fatigue 0 (0) 2 (20) 0 (0) 0 (0) 1 (33) 1 (11) 0 (0) 0 (0) 4 (9)

Rosen et al 35 Safety of Ganitumab Plus Targeted or Cytotoxic Agents Downloaded from Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Cohort 1 Cohort 5 Cohort 2 Cohort 6 Cohort 3 Cohort 7 Cohort 4 Cohort 8 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369 Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab + + + + + + + + 400 mg BID 400 mg BID 6 mg/kg Q2W 6 mg/kg Q2W 150 mg QD 150 mg QD 1000 mg/m2 1000 mg/m2

clincancerres.aacrjournals.org Sorafenib Sorafenib Panitumumab Panitumumab Erlotinib Erlotinib Gemcitabine Gemcitabine Total Patients, n (%) (n=3) (n=10) (n=6) (n=4) (n=3) (n=9) (n=8) (n=3) (n=46) Anemia 1 (33) 2 (20) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (33) 4 (9) Rash 0 (0) 1 (10) 0 (0) 1 (25) 0 (0) 0 (0) 0 (0) 0 (0) 2 (4) Intestinal obstruction 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (11) 1 (13) 0 (0) 2 (4) Hypomagnesemia 1 (33) 0 (0) 2 (34) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (4) Dehydration 0 (0) 1 (10) 0 (0) 0 (0) 0 (0) 1 (11) 0 (0) 0 (0) 2 (4) AE, adverse event; BID, twice daily; Q2W, every 2 weeks; QD, once daily. *Safety analysis set includes patients who received ≥1 dose of ganitumab. †AEs listed include those occurring in ≥4% of all patients. on September 27, 2021. © 2012American Association for Cancer Research.

Rosen et al 36 Safety of Ganitumab Plus Targeted or Cytotoxic Agents Downloaded from

Table 3. Pharmacokinetic Parameter Estimates of Ganitumab After Coadministration With Sorafenib, Panitumumab, Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369 Erlotinib, or Gemcitabine* clincancerres.aacrjournals.org Cohort 1 Cohort 5 Cohort 2 Cohort 6 Cohort 3 Cohort 7 Cohort 4 Cohort 8 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg 6 mg/kg 12 mg/kg Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab Ganitumab + + + + + + + + 400 mg BID 400 mg BID 6 mg/kg Q2W 6 mg/kg Q2W 150 mg QD 150 mg QD 1000 mg/m2 1000 mg/m2 Parameter, Sorafenib Sorafenib Panitumumab Panitumumab Erlotinib Erlotinib Gemcitabine Gemcitabine Mean (SD) (n=2) (n=9) (n=5) (n=3) (n=3) (n=4) (n=8) (n=3)

Cmax, µg/mL 106 (0) 231 (54.1) 129 (42.5) 359 (84.6) 133 (32.0) 251 (64.1) 114 (23.6) 264 (28.0)

Research. † AUCτ, h·µg/mL 388 (NA)* 879 (337) 643 (205) 1430 (234) 529 (102) 1250 (186) 592 (168) 1170 (266)

CL, mL/d/kg 17.0 (NA)* 16.6 (7.49)† 10.7 (5.02) 8.94 (1.51) 12.1 (1.85) 10.1 (1.24) 11.2 (3.46) 10.8 (2.30)

AUCτ, area under the concentration versus time curve for a dosing interval; BID, twice daily; CL, systemic clearance; Cmax, maximum observed serum concentration after dosing; Cmin, minimum observed serum concentration after dosing; NA, not assessable; Q2W, every 2 weeks; QD, once daily. *Data were available from only 1 patient. †Data available from only 8 patients.

Rosen et al 37 Safety of Ganitumab Plus Targeted or Cytotoxic Agents Downloaded from

Table 4. Pharmacokinetic Parameter Estimates of Sorafenib, Panitumumab, Erlotinib, and Gemcitabine After Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369 Coadministration With Ganitumab clincancerres.aacrjournals.org Mean (SD) Mean (SD) Agent Week* Dose Regimen n Cmax, µg/mL AUCτ, h·µg/mL

Sorafenib 5 400 mg BID 2–4 5.36 (4.03) 37.0 (14.0)

Panitumumab 5 6 mg/kg Q2W 8 197 (52.3) 35,280 (8952)

Erlotinib 5 150 mg QD 6–9 1.59 (1.21) 33.5 (24.3)

Gemcitabine 5 1000 mg/m2 QW 11 11.0 (12.5) 6.38 (5.69)

dFdU† 11 31.3 (7.58) 220 (48.1)

AUCτ, area under the concentration versus time curve for a dosing interval; BID, twice daily; Cmax, maximum observed serum concentration after dosing; Q2W, every 2 weeks; QD, once daily; QW, once weekly. *Week 1 without ganitumab or week 5 with ganitumab. †2’2’–difluorodeoxyuridine (dFdU) is a metabolite of gemcitabine.

Rosen et al 38 Author Manuscript Published OnlineFirst on April 17, 2012; DOI: 10.1158/1078-0432.CCR-11-3369 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Safety of Ganitumab Plus Targeted or Cytotoxic Agents

1 Figure Legends

2 Figure 1. The best-result changes from baseline in sum of the cross-products of the

3 longest diameters of index lesions among evaluable patients with

4 measureable disease (n=35) per World Health Organization criteria and

5 independent central review for patients who received ganitumab

6 combined with sorafenib, panitumumab, erlotinib, or gemcitabine. Four

7 patients are not included: 1 colon cancer patient (ganitumab 6 mg/kg +

8 panitumumab) had progressive disease due to new lesions; 1 esophageal

9 cancer patient (ganitumab 6 mg/kg + erlotinib) had progressive disease

10 due to new lesions; 1 breast cancer patient (ganitumab 6 mg/kg +

11 gemcitabine) with only nonindex lesions had stable disease; and 1

12 ovarian cancer patient (ganitumab 12 mg/kg + sorafenib) had progressive

13 disease due to new lesions. CUO=carcinoma of unknown origin;

14 GE=gastroesophageal; HC=hepatocellular carcinoma; HGSL=high grade

15 sarcoma, leiomyosarcoma; NSCLC=non–small-cell lung cancer;

16 SC=sacrum chordoma; SCCA=squamous cell carcinoma of the anus;

17 SCHN=squamous cell head/neck; SCLC=small-cell lung cancer.

18 Figure 2. Mean (SD) change from baseline in serum total IGF1 (A) and IGFBP-3

19 (B). IGF1, insulin-like growth factor 1; IGFBP-3, insulin-like growth

20 factor–binding protein 3.

Rosen et al 39

Downloaded from Maximum Change From Baseline in SLD, % –70 –60 –50 –40 –30 –20 –10 10 20 30 40 50 60 70 0 Author manuscriptshavebeenpeerreviewedandacceptedforpublicationbutnotyetedited. Author ManuscriptPublishedOnlineFirstonApril17,2012;DOI:10.1158/1078-0432.CCR-11-3369 Ovarian

NSCLC Ganitumab +Sorafenib SCCA

clincancerres.aacrjournals.org HC (n=10) HGSL Endometrial Thyroid SC Neuroendocrine Endometrial Ganitumab +Panitumumab Thyroid Colon Pancreatic on September 27, 2021. © 2012American Association for Cancer (n=8)

Research. GE Junction Colon Colon Rectal Colon Ganitumab +Erlotinib SCL Ovarian

Colon (n=7) Breast Carcinoid NSCLC Breast

SCL Ganitumab +Gemcitabine SCHN Colon CUO (n=10) Colon Progressive disease Stable disease Partial response Ovarian Colon NSCLC Ovarian Prostate Author Manuscript Published OnlineFirst on April 17, 2012; DOI: 10.1158/1078-0432.CCR-11-3369 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.

Figure 2

A 2.0 Ganitumab 6 mg/kg Ganitumab 12 mg/kg

1.5

1.0 Serum IGF1 Level Relative to Baseline

0.5 0 10 20 30 40 50 60 70 80 Time, d

B 2.0 Ganitumab 6 mg/kg Ganitumab 12 mg/kg

1.5

1.0 Serum IGFBP-3 Level Relative to Baseline

0.5 0 10 20 30 40 50 60 70 80 Time, d

Safety and Pharmacokinetics of Ganitumab (AMG 479) Combined With Sorafenib, Panitumumab, Erlotinib, or Gemcitabine in Patients With Advanced Solid Tumors

Lee S. Rosen, Igor Puzanov, Greg Friberg, et al.

Clin Cancer Res Published OnlineFirst April 17, 2012.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-11-3369

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