Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab

Home , Ofatumumab

Published OnlineFirst July 2, 2010; DOI: 10.1158/1078-0432.CCR-10-0570 Published OnlineFirst on August 24, 2010 as 10.1158/1078-0432.CCR-10-0570

Report from the FDA Clinical Cancer Research U.S. Food and Drug Administration Approval: Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab

Steven J. Lemery1, Jenny Zhang2, Mark D. Rothmann2, Jun Yang3, Justin Earp3, Hong Zhao3, Andrew McDougal1, Anne Pilaro1, Raymond Chiang1, Joseph E. Gootenberg1, Patricia Keegan1, and Richard Pazdur1

Abstract Purpose: To describe the data and analyses that led to the U.S. Food and Drug Administration (FDA) approval of ofatumumab (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. Experimental Design: The FDA reviewed the results of a planned interim analysis of a single-arm trial, enrolling 154 patients with CLL refractory to fludarabine, and a supportive dose-finding, activity-estimating trial in 33 patients with CLL. Patients in the primary efficacy study received ofatumumab weekly for eight doses, then every 4 weeks for an additional four doses; patients in the supportive trial received four weekly doses. In the primary efficacy study, endpoints were objective response rate and response duration. Results: For regulatory purposes, the primary efficacy population consisted of 59 patients with CLL refractory to fludarabine and alemtuzumab. In this subgroup, the investigator-determined objective response rate was 42% [99% confidence interval (CI), 26–60], with a median duration of response of 6.5 months (95% CI, 5.8–8.3); all were partial responses. The most common adverse reactions in the primary efficacy study were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. Infusion reactions occurred in 44% of patients with the first infusion (300 mg) and 29% with the second infusion (2,000 mg). The most common serious adverse reactions were infections, neutropenia, and pyrexia. Conclusions: On October 26, 2009, the FDA granted accelerated approval to ofatumumab for the treatment of patients with CLL refractory to fludarabine and alemtuzumab, on the basis of demonstration of durable tumor shrinkage. Clin Cancer Res; 16(17); 4331–8. ©2010 AACR.

Chronic lymphocytic leukemia (CLL) is a clonal disor- patients with CLL has been based on a clinically mean- der of B cells with a variable clinical course. Median sur- ingful prolongation of progression-free survival (PFS) ac- vival is longer than 10 years4; however, reported median companied by an acceptable safety profile; whereas survival is only 2 to 3 years for patients with high-risk accelerated approval has been granted on the basis of disease (Rai category III or IV or Binet stage 3; ref. 1). Re- durable overall response rates (ORR) in patients with ported survival in CLL patients whose disease is refractory CLL, which has progressed following available therapy. to multiple drugs is shorter; in one report, median survival In order to be considered for accelerated approval, a was 8 months in patients with CLL refractory to fludara- drug that shows an effect on a surrogate endpoint that bine and alemtuzumab (2). is reasonably likely to predict clinical benefit must treat In the past decade, regular U.S. Food and Drug a serious or life-threatening disease or condition and Administration (FDA) approval for the treatment of show an advantage over available therapy (3). Addition- ally, the commercial manufacturer must commit to study the drug further to verify and characterize the pre- Authors' Affiliations: 1Office of Oncology Drug Products, Office of New dicted clinical benefit (3). Drugs; 2Office of Biostatistics; and 3Office of Clinical Pharmacology, Alemtuzumab received accelerated approval in 2001 Center for Drug Evaluation and Research, U.S. Food and Drug and regular approval in 2007. Accelerated approval was Administration, Silver Spring, Maryland based on the results of three single-arm studies enrolling Corresponding Author: Steven Lemery, Division of Biological Oncology Products, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2374, Silver Spring, MD 20993. Phone: 301-796-2276; Fax: 301-796-9849; E-mail: [email protected]. 4 Horner MJ, Ries LAG, Krapcho M, et al., editors. SEER Stat Fact Sheets, doi: 10.1158/1078-0432.CCR-10-0570 1975-2006. Bethesda (MD): National Cancer Institute; [cited 2007 Jul ©2010 American Association for Cancer Research. 27]. Available from: http://seer.cancer.gov/.

www.aacrjournals.org 4331

Lemery et al.

149 patients with CLL and progressive disease following Nonclinical Pharmacology and Toxicology alkylating agents and fludarabine. The rates of durable objective responses (ORR) in the three studies ranged Ofatumumab binds specifically to the CD20 molecule, from 21 to 33% (4). Regular approval was based on supe- which is expressed on normal B lymphocytes (pre-B– to rior PFS [HR 0.58 (95% confidence interval [CI], 0.43– mature B–lymphocyte) and on B-cell CLL tumor cells. 0.77), P < 0.0001 stratified log-rank test] in a randomized The CD20 molecule is not shed from the cell surface active-controlled study comparing alemtuzumab to chlor- and is not internalized following antibody binding (6). ambucil in previously untreated patients with CLL (4). The Fab domain of ofatumumab binds to the CD20 Alemtuzumab also showed an improvement in ORR molecule, and the Fc domain mediates immune effector (83% versus 55%) and complete response rates (24% functions to result in B-cell lysis in vitro (6). Possible me- versus 2%) compared with chlorambucil (4). chanisms of action for ofatumumab include complement- The FDA approved bendamustine in 2008 on the basis dependent cytotoxicity and antibody-dependent cell- of superior PFS [HR 0.27 (95% CI, 0.17-0.43), P < 0.0001] mediated cytotoxicity. in a randomized active-controlled study comparing bend- Nonclinical data submitted in support of the applica- amustine to chlorambucil in previously untreated patients tion included tissue-binding studies in human and cyno- with CLL. In the study, bendamustine also showed an molgus monkey tissue panels, evaluation of in vitro improvement in ORR (59% versus 26%) and complete pharmacologic activity (receptor binding, lysis of CD20- response rates (8% versus <1%) compared with chloram- expressing cells), in vivo pharmacologic activity (antitumor bucil (5). activity in severe combined immunodeficient mice bearing In addition to bendamustine and alemtuzumab, the fol- human tumor xenografts, characterization of B-cell deple- lowing drugs are approved for the treatment of patients tion in treated monkeys), pharmacokinetic studies in cy- with CLL: fludarabine, cyclophosphamide, and chloram- nomolgus monkeys, and subacute (4-week) and chronic bucil. These drugs were approved on the basis of durable (7-month) toxicology studies in cynomolgus monkeys. objective tumor responses prior to the codification of the The major ofatumumab toxicities observed in nonclinical accelerated approval regulations. studies were extensions of its expected pharmacologic The Biologics License Application (BLA) for ofatumu- activity, that is, the severe and prolonged depletion of mab was submitted on January 30, 2009. The application B lymphocytes both in the circulation and in the major contained the interim results of a single-arm, fixed-dose, lymphoid organs (follicular germ centers of the spleen, multicenter trial (Hx-CD20-406), and the final results cortical lymph nodes, and Peyer's patches in the gastroin- of a multicenter, sequential dose-escalating cohort and testinal tract). Other toxicities observed in the 7-month re- activity-estimating trial (Hx-CD20-402), which used a peat-dose cynomolgus monkey toxicity study included shorter treatment duration (4 doses versus 12 doses) than sporadic, nonsevere infusion reactions, hematologic the primary efficacy study. Both trials enrolled adults with changes including B-cell depletion, mild hemolytic ane- CLL who had relapsed following, or were refractory to, mia, and changes in neo- and recall-antigen responses. one or more standard treatments. The BLA was supported by safety information from several trials enrolling 151 patients with follicular lymphoma or diffuse large B-cell Clinical Pharmacology lymphoma, 282 patients with rheumatoid arthritis or chronic obstructive pulmonary disease, and 28 patients Pharmacokinetic data were obtained from 146 patients with CLL who received ofatumumab in combination with with refractory CLL who received a 300-mg initial dose chemotherapy. The primary efficacy trial used the highest followed by seven weekly and four monthly infusions of dose and longest duration of ofatumumab in the clinical 2,000 mg (6). The Cmax and AUC(0−∞) after the eighth safety database. infusion in study Hx-CD20-406 were approximately 40% and 60% higher than after the fourth infusion in study Hx-CD20-402 (6). The mean volume of distribution Chemistry, Manufacturing, and Controls at steady-state (Vss) values ranged from 1.7 to 5.1 L (6). Ofatumumab is eliminated through both a target- Ofatumumab is an immunoglobulin G1 (IgG1) kappa independent route and a B-cell–mediated route (6). Ofa- human monoclonal antibody with a molecular weight tumumab exhibited dose-dependent clearance in the dose of approximately 149 kDa (6). The antibody was gene- range of 100 to 2,000 mg (6). Because of the depletion rated via transgenic mouse and hybridoma technology of B cells, the clearance of ofatumumab decreased sub- and is produced in a recombinant murine cell line stantially after subsequent infusions compared with the (NS0) using standard mammalian cell cultivation and first infusion (6). The mean clearance between the 4th purification technologies (6). It is supplied as a sterile, and 12th infusions was approximately 0.01 L/h and ex- colorless, preservative-free liquid concentrate at a con- hibited large intersubject variability with CV% greater centration of 20 mg/mL in a 5 mL volume of solution than 50% (6). The mean t1/2 between the 4th and 12th for intravenous infusion in a 10 mL single use vial infusions was approximately 14 days (range: 2.3 to 61.5 (100 mg/vial; ref. 6). days; ref. 6).

4332 Clin Cancer Res; 16(17) September 1, 2010 Clinical Cancer Research

FDA Approval Summary of Ofatumumab

No dosage adjustment was determined to be necessary the risk of serious infusion reactions; all subsequent doses on the basis of body weight, age, gender, or renal impair- were 2,000 mg. Premedication with an oral or intravenous ment. Patient age (ranging from 21 to 86 years) and creat- antihistamine, oral acetaminophen, and an intravenous inine clearance at baseline (ranging from 33 to 287 mL/ corticosteroid (100 mg prednisolone or equivalent) was min) did not have a clinically important effect on ofatu- administered prior to each dose; the dose of corticosteroid mumab pharmacokinetics (6). Gender did not influence administered prior to doses 3 to 8 and 10 to 12 could be ofatumumab pharmacokinetics after correcting for body reduced on the basis of the absence of infusional toxicity weight differences. Although volume of distribution and on preceding doses. clearance increased with body weight (6), it did not ex- Ofatumumab dosing was terminated early for a critical plain intersubject variation for the clinical endpoint. adverse event, pregnancy, administration of alternative an- In patients with CLL refractory to fludarabine and alem- ticancer therapy, withdrawal of consent, or investigator tuzumab, the median decrease in circulating CD19-positive discretion. Critical adverse events included the following: B cells was 91% (n = 50) with the 8th infusion and 85% occurrence of a treatment-related grade 4 or greater ad- (n = 32) with the 12th infusion (6). The time to recovery verse event on any noninfusion day (excluding infections); of lymphocytes, including CD19-positive B cells, to nor- a grade 3 or greater treatment-related adverse event that mal levels could not be determined using the data submit- prevented resumption of an ofatumumab infusion; sec- ted to the BLA. ond occurrence of grade 3 or greater bronchospasm during an infusion; or the third occurrence of the same adverse Clinical Studies event of grade 3 or greater in severity during an infusion. Toxicity was managed by reducing the rate of infusion, Materials and methods suspension of an infusion for management of infusional The major efficacy (Hx-CD20-406) and dose-finding toxicity, or by withholding the ofatumumab dose for other (Hx-CD20-402) trials were conducted by Genmab A/S. toxicities. Study Hx-CD20-402 was a multicenter, sequential dose- Protocol-specified monitoring included assessment of escalating and activity-estimating trial that enrolled a total CLL status at baseline, every 4 weeks until week 28, then of 33 patients with previously treated CLL. Three dose co- every 3 months until month 24. CLL disease-status assess- horts were studied with an expansion of the highest dose ments consisted of measurements of lymph nodes, liver, cohort to further evaluate antitumor activity. The treat- and spleen by physical examination; complete blood ment regimen was limited to four weekly doses as follows: counts including hemoglobin, platelet, neutrophil, and level 1 received 100 mg week 1 and 500 mg weeks 2 to 4 lymphocyte counts; and queries for constitutional symp- (n = 3); level 2 received 300 mg week 1 and 1,000 mg on toms. Bone marrow aspiration and biopsy and computed weeks 2 to 4 (n = 3); and level 3 received 500 mg on week tomography (CT) scan of the neck, chest, abdomen, and 1 and 2,000 mg weeks 2 to 4 (n = 27). pelvis were obtained at baseline and for confirmation of Hx-CD20-406 was an open-label, multicenter, interna- a complete response (CR). All adverse events were collect- tional, single-arm, fixed-dose trial. Eligibility was limited ed up to 24 months following study entry; serious adverse to patients 18 years of age or older, Eastern Cooperative events, resulting in hospitalization or death, and peripher- Oncology Group (ECOG) performance status (PS) 0 to al B-lymphocyte counts were collected for 48 months or 2, with CLL requiring treatment as defined in the NCI until initiation of alternative anti-CLL therapy, whichever Working Group (1996 NCIWG) guidelines (7). All pa- occurred earlier. tients were required to be refractory to fludarabine (mini- The primary endpoint was objective response rate mum of two cycles), and to be refractory to alemtuzumab (ORR), based on the 1996 NCIWG criteria for response, [double refractory (DR) subgroup], or to be refractory to occurring at any time between the first dose of ofatumu- fludarabine and have at least one lymph node >5 cm mab through week 24, as determined by an Independent [bulky fludarabine refractory (BFR) subgroup]. A total of Endpoints Review Committee (IRC). The IRC was com- 16 patients met entry criteria for earlier versions of the posed of five independent board-certified oncologists or study but could not be considered DR or BFR. Drug refrac- hematologists experienced with CLL. The committee was toriness was defined as the failure to achieve at least a par- to be provided with clinical data and determine the level tial response to, or disease progression within 6 months of response and when progression occurred according to of, the last dose of fludarabine or alemtuzumab. The pri- NCIWG guidelines. CT scans were not included in the re- mary efficacy population was a prespecified subgroup of sponse determinations. An independent radiology review those enrolled in Hx-CD20-406, the fludarabine- and was conducted by an independent imaging core laboratory alemtuzumab-refractory subgroup, based on presubmis- (ICON medical imaging). A single board-certified radio- sion discussions with the FDA. logist reviewed all imaging data to: (1) confirm complete Ofatumumab was administered as an intravenous infu- remissions and (2) verify the presence of bulky lymphade- sion in 1,000 mL of 0.9% sodium chloride injection, USP, nopathy at study entry. weekly for the first eight doses (doses 1 to 8), then every The protocol-specified criteria for determination of ORR 4 weeks for the remaining four doses (doses 9 to 12). The (complete plus partial responses [PR]) were based on the first dose of ofatumumab was reduced (300 mg) to reduce 1996 NCIWG guidelines (7). The criteria for a PR required

www.aacrjournals.org Clin Cancer Res; 16(17) September 1, 2010 4333

Lemery et al.

the following: ≥50% decrease in peripheral blood lym- IRC review identified 59 patients as DR, 79 patients as phocyte counts; ≥50% reduction in lymphadenopathy BFR, and 16 patients as “other.” This review focuses on [sum of the perpendicular products of all palpable lymph the efficacy results from the IRC-confirmed DR group, nodes (the largest lymph node in each area was to be mea- the patient population that satisfied the regulatory defini- sured)]; ≥50% reduction in hepatomegaly or splenomega- tion of unmet medical need. ly from baseline measurements if there was hepatomegaly The overall population in study Hx-CD20-406 was or splenomegaly at baseline; and at least one of the fol- heavily pretreated. In the DR group (n = 59), the median lowing: polymorphonuclear leukocyte count ≥1,500/mcL number of prior therapies was 5 and the range was 1 to 14. or 50% improvement over baseline; platelet count Two patients in the DR group received one prior therapy; >100,000/mcL or 50% improvement over baseline; or he- both of these patients received fludarabine combined with moglobin >11 gm/dL or 50% improvement over baseline alemtuzumab. Baseline characteristics and prior treatment without transfusions with a response duration of at least history are summarized for the DR subgroup and for the 56 days. The criteria for a CR required the absence of overall study population in Tables 1 and 2, respectively. lymphadenopathy, hepatomegaly, and splenomegaly by Nearly all (97%) patients enrolled in study Hx-CD20- physical examination; the absence of constitutional symp- 406 were white, and most were men (72%). Median time toms; normal hematological counts with lymphocytes less in years from original diagnosis to enrollment into study than 4,000/mcL for at least 56 days; and a bone marrow Hx-CD20-406 was 6.3 years. ZAP70 was not assessed at aspirate (2 months after CR criteria were met) showing the baseline. Approximately one quarter (26%) of the study absence of lymphoid nodules, <30% lymphocytes, and population was accrued from U.S. sites. normocellularity for age. The protocol also required that Table 2 shows that nearly all patients in the DR group, a CT scan be done 8 weeks after a patient fulfilled the re- as well as the overall study population, received an alkylat- quirements of a CR (to confirm the CR). ing agent–containing regimen. More than 50% of the pa- Additional endpoints were duration of response (DOR), tients in study Hx-CD20-406 received prior rituximab; PFS, time-to-next CLL therapy, overall survival, and reduc- however, data were not collected to determine whether tion in tumor size (the percentage change in the sum of these patients were rituximab refractory. the products of the diameters). The DOR was defined as The magnitude of the treatment effect on ORR, as deter- the time from the initial response to disease progression, mined by the individual IRC members, IRC consensus de- or death. For the analysis of DOR, the following scenarios termination, investigators, and FDA, differed. The ORR were censored: no progression at the end of the trial; treat- and DOR determined by the investigator, the IRC consen- ment discontinued for undocumented progression, toxici- sus finding, and FDA are summarized in Table 3. The ty, or other reasons; new anticancer therapy started; and estimated DOR of response in the DR population was death or progression after two or more consecutive missed 6.5 months. visits. Unexpected findings in this trial were the high rate of The planned study sample size of 100 patients per treat- discordance in tumor-response assessment between the ment subgroup (DR and BFR) was based on the assump- individual IRC members and the higher ORR as deter- tion of 30% ORR in the DR subgroup and the probability mined by the IRC as compared with that determined by that the exact 2-sided 99% CI would exclude a response the investigators. Investigator assessments from study rate of less than 15% with 63% power based on 66 patients in the interim analysis and 92% power based on 100 patients in the final analysis. Table 1. Demographics of patients enrolled in – Results study Hx-CD20 406 DR (n = 59) Total (N = 154) Efficacy The initial activity-estimating trial, Hx-CD20-402, eval- Gender uated 27 patients at the highest dose cohort. There was a Female 25% 28% 42% PR rate, with a median duration of response of 16 Male 75% 72% n weeks across the entire study ( = 33). One response Age n was reported in the 500 mg ( = 3) cohort, none reported ≥65 years 46% 43% n in the 1,000 mg ( = 3) cohort, and 13 responses reported Median in years (range) 64 (41–86) 63 (41–86) among the 27 patients enrolled at the 2,000-mg dose co- ECOG PS hort. Because of the relatively modest duration of re- 0 46% 36% sponses observed with four weekly doses, the duration 1 32% 45% of treatment was increased in the Hx-CD20-406 trial. 2 20% 19% The Hx-CD20-406 trial enrolled 154 patients at the time 32%1% of the planned interim analysis. The IRC conducted an Time from last CLL treatment (years) audit of patient records and case report forms to confirm Median 0.36 (0.08–1.67) 0.39 (0.08–6.5) investigator-assigned patient subgroup classification; the

4334 Clin Cancer Res; 16(17) September 1, 2010 Clinical Cancer Research

FDA Approval Summary of Ofatumumab

Table 2. Pretreatment history in study Hx-CD20–406

Type of prior regimen DR (n = 59) Total (N = 154)

Alkylating agent 93% 94% Bendamustine alone or bendamustine-containing regimen 3% 6% Fludarabine 100% 100% Fludarabine-containing combination regimen* 85% 81% Alemtuzumab 100% 55% Rituximab 59% 57%

*The other drug could include a monoclonal antibody, steroid, or chemotherapy (or a combination of different therapies).

Hx-CD20-406 were derived from assessments of response IRC. The FDA clinical reviewer did not use the strictest at individual visits and not from an overall response as- interpretation of the 1996 NCIWG criteria under which sessment provided by the investigators. Fifty-eight percent the detection of any new node (for example, a 1 × 1–cm of 59 patients in the DR and of the 79 patients in the BFR lymph node that regressed at the next visit) would desig- subgroups underwent adjudication by a third IRC member. nate a progression event. Adjudication was required when there was disagreement between the initial IRC reviewers about response assess- Safety results ment, date of onset of the response, or date of progression. Study Hx-CD20-406 was the only study submitted to The high rate of disagreement was unexpected, given that the BLA that evaluated ofatumumab at the recommended all IRC members used the same information for lympho- doses and schedule. Because the data primarily were de- cyte measurements, hematology laboratory values, and rived from an uncontrolled study, only a descriptive anal- investigator-recorded liver, spleen, and lymph node mea- ysis of safety could be done. In study Hx-CD20-406, 90% surements. There was insufficient information captured of patients received at least 8 infusions of ofatumumab, during the IRC review to allow the FDA to determine the and 55% received 12 infusions. The most common rea- source of the disagreements between IRC members. sons for stopping treatment was disease progression and These differences seem to have been related to individ- adverse reactions, mostly due to infections. ual interpretation of the 1996 NCIWG criteria as applied The most common adverse reactions (≥10%) in study to the same set of data. The 1996 NCIWG response criteria Hx-CD20-406 were neutropenia, pneumonia, pyrexia, were written such that a strict application of the criteria cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, would result in few responders, even in a drug with nota- bronchitis, and upper respiratory tract infections. Table 4 ble activity. For example, the criteria for disease progres- shows adverse reactions that occurred in ≥5% of the total sion could be met with new lymphadenopathy of study population. The incidence of neutropenia as an relatively small size, even if transiently enlarged in a pa- adverse reaction is not described in the table because the tient with an intercurrent infection. laboratory data gave a more accurate description of neu- The FDA clinical reviewer's determination of ORR, tropenia occurring after ofatumumab treatment. based on data captured in case report forms and study da- Infusion reactions, including sequelae of such reactions, ta sets, yielded an ORR in the DR subgroup that was sim- occurred frequently during the ofatumumab development ilar to that of the investigators and lower than that of the program (all oncology and nononcology studies). Infusion

Table 3. Efficacy results for study Hx-CD20–406

Protocol HX-CD20–406 analysis subgroup and outcomes Investigator-determined IRC-determined FDA-determined

Primary efficacy subgroup (n = 59) (n = 59) (n = 56) DR ORR 42% (25/59) 54% (32/59) 41% (23/56) 99% CI 26%–60% 37%–71% 25%–59% Median response duration (months) 6.5 7.1 6.5 Supportive subgroup (n = 79) (n = 79) — BFR 34% (27/79) 44% (35/79) — ORR (99% CI) 21%–49% 30%–59% —

www.aacrjournals.org Clin Cancer Res; 16(17) September 1, 2010 4335

Lemery et al.

Table 4. Per-patient incidence of adverse reactions occurring in ≥5% of patients

Body system and/or adverse event* DR group (n = 59) Total population (N = 154) All grades Grade ≥3 All Grades Grade ≥3

Infections and infestations Pneumonia† 25 15 23 14 Upper respiratory tract infection 3 0 11 0 Bronchitis 19 2 11 <1 Sepsis‡ 10 10 8 8 Nasopharyngitis 8 0 8 0 Herpes zoster 7 2 6 1 Sinusitis 3 2 5 2 Blood and lymphatic system disorders Anemia 17 8 16 5 Psychiatric disorders Insomnia 10 0 7 0 Nervous system disorders Headache 7 0 6 0 Cardiovascular disorders Hypertension 8 0 5 0 Hypotension 3 0 5 0 Tachycardia 7 2 5 <1 Respiratory, thoracic, and mediastinal disorders Cough 19 0 19 0 Dyspnea 19 5 14 2 Gastrointestinal disorders Diarrhea 19 0 18 0 Nausea 12 0 11 0 Skin and subcutaneous tissue disorders Rash§ 17 2 14 <1 Urticaria 5 0 8 0 Hyperhidrosis 5 0 5 0 Musculoskeletal and connective tissue disorders Back pain 12 2 8 1 Muscle spasms 3 0 5 0 General disorders and administration site conditions Pyrexia 25 5 20 3 Fatigue 15 0 15 0 Edema peripheral 8 2 9 <1 Chills 10 0 8 0

*Adapted from MedDRA version 9.0. †Pneumonia includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. ‡Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. §Rash includes rash, rash macular, and rash vesicular.

reactions were less common after the first two infusions. HxCD20-406, infusion reactions occurred in 44% of Serious infusion-related reactions or sequelae included patients on the day of the first infusion (300 mg), and bronchospasm, dyspnea, laryngeal edema, pulmonary 29% on the day of the second infusion (2,000 mg). edema, flushing, hypertension, hypotension, syncope, car- Infections frequently occurred after treatment with ofa- diac ischemia and/or infarction, back pain, abdominal tumumab. In study Hx-CD20-406, 70% of patients expe- pain, pyrexia, rash, urticaria, and angioedema. In a sepa- rienced bacterial, viral, or fungal infections. A total of 29% rate study of patients with moderate-to-severe chronic of the study population experienced ≥grade 3 infections, obstructive pulmonary disease, two of five patients devel- of which 12% were fatal. The proportion of fatal infections oped grade 3 bronchospasm during an infusion. In study in the DR group was 17%. One patient with CLL died of

4336 Clin Cancer Res; 16(17) September 1, 2010 Clinical Cancer Research

FDA Approval Summary of Ofatumumab

progressive multifocal leukoencephalopathy after receiv- the FDA in the May 29, 2009 advisory committee meeting, ing ofatumumab treatment in study Hx-CD20-406. One the FDA could not determine whether ofatumumab is bet- patient with rheumatoid arthritis died of fulminant hepa- ter than alemtuzumab in the absence of a randomized titis B infection after receiving ofatumumab in a non- comparative trial. oncology study. The FDA used the investigator-determined ORR and Neutropenia frequently occurred or was exacerbated DOR for regulatory decision making. The FDA elected following ofatumumab treatment. Of 108 patients with not to use the IRC determination for several reasons, in- normal baseline neutrophil counts at baseline, 42% devel- cluding the high rate of disagreement across reviewers, oped grade 3 or greater neutropenia. Nineteen (18%) de- the lack of direct evaluation of tumor measurements based veloped grade 4 neutropenia. Some patients experienced on lack of serial radiographs for independent analysis, the new onset grade 4 neutropenia for more than 2 weeks in relatively minor contribution of hematologic laboratory duration. data to the determination of ORR, and the FDA's independent review of the case reports forms and supporting Discussion laboratory data. The magnitude of the ORR in study Hx-CD20-406 could The FDA granted subpart E (accelerated) approval under not be reproduced by multiple groups (investigators, IRC 21 CFR 601.41 for ofatumumab on October 26, 2009. Ac- members, and FDA) given the same set of information. celerated approval may be granted only for a drug that This lack of consistency seemed to be due to variability treats a serious or life-threatening illness and provides in interpretation and application of the 1996 NCIWG cri- meaningful therapeutic benefit to patients over existing teria for response assessments. In order to have consistent treatments (i.e., fulfills an unmet medical need), on the application, tumor-response criteria should ideally be un- basis of the demonstration of an effect on a surrogate end- ambiguous such that given the same data, similar conclu- point that is reasonably likely to predict clinical benefit. sions will be drawn by all response assessors. Such The FDA concluded that the subpopulation of patients consistent application of the response criteria was not ob- studied in Hx-CD20-406 who were refractory to fludara- served during the review of study Hx-CD20-406. Criteria bine and alemtuzumab, more than 90% of whom also re- that allow for such variability in interpretation are gener- ceived prior therapy that included an alkylating agent and ally appropriate for the overall practice of medicine; how- who received a median of five prior treatments prior to en- ever, the evidentiary standard required for regulatory rollment in the Hx-CD20-406 study, was a patient popu- decision making is generally higher than those employed lation with an unmet medical need. The ORR effect size in for clinical decision making, or for informing the overall the DR population of 42%, with an estimated duration of practice of medicine. response of 6.5 months supported by antitumor activity in Since the Hx-CD20-406 study was started, the NCIWG other patients with CLL, was considered reasonably likely published new (2008) criteria that now recommend the to predict clinical benefit both by the FDA and by the ma- use of CT scans in the response assessments of patients jority of the May 2009 Oncology Drugs Advisory Commit- with CLL for clinical trials (9). On the basis of these re- tee (10-to-3 vote). vised criteria and advice from the May 2009 Oncology For the product label, the FDA limited the description of Drugs Advisory Committee (ODAC), the FDA will expect efficacy to the subgroup that was refractory to fludarabine that serial CT scans be obtained in new studies in order to and alemtuzumab, as this was the population that met the make labeling claims for ORR in patients with advanced regulatory definition of unmet medical as required for ac- CLL. The FDA notes, however, that certain aspects of the celerated approval. For accelerated approval, drugs must revised 2008 criteria may still be problematic. For exam- provide meaningful therapeutic benefit to patients over ex- ple, if one lymph node increases in size from 1 cm to isting treatments. In settings where existing treatments are 1.5 cm during the first 2 months of a response, a patient available, randomized studies are necessary to grant accel- may not be classified as a responder, even if the node re- erated approval on the basis of an effect on a surrogate solves in size at the next visit and all other nodes have de- endpoint. The randomized studies should show that the creased in size. Additionally, a single new node of 1 cm in new drug provides meaningful therapeutic benefit over diameter during the first 2 months of a response can des- an existing treatment. This comparative effectiveness stan- ignate the patient as a nonresponder. dard exists for accelerated approval but does not exist for Occurrences such as these were not considered to nullify regular FDA approval of a drug or biological drug. a response in study Hx-CD20-406, as clinical judgment The applicant did not satisfactorily establish that pa- was allowed to override the explicit rules of the NCIWG. tients with BFR disease met the regulatory definition of Optimally, the NCIWG criteria should be modified for unmet medical need. The Hx-CD20-406 protocol required use in clinical trials so that the rules explicitly state what that patients with bulky disease be refractory to fludara- deviations from the criteria are acceptable for the determi- bine and thus may have received only one previous treat- nation of response or progression. Such codification of the ment regimen. However, responses to alemtuzumab were rules will permit a more accurate description of the treat- reported in 76% of 33 previously untreated patients with ment effect of a drug. The FDA encourages sponsors to lymph nodes ≥5 cm (CAM307 study; ref. 8). As stated by discuss such deviations from the response criteria prior

www.aacrjournals.org Clin Cancer Res; 16(17) September 1, 2010 4337

Lemery et al.

to initiating a clinical study intended to support labeling infections. In patients with indolent hematologic malig- claims based on PFS or ORR in patients with CLL. nancies, in which median survival is measured in years, The FDA acknowledges that uncertainty exists in the demonstration of effects on overall survival may not be ability of a surrogate endpoint to predict direct clinical as practical as an approval endpoint; however, evidence benefit, and therefore, under 21 CFR 601.41, additional of no apparent detrimental effects on survival is generally clinical studies are required to verify and describe the clin- required as an assessment of product safety. ical benefit of the drug. GlaxoSmithKline has committed Enrollment of the confirmatory GlaxoSmithKline trial to conduct a confirmatory randomized trial of ofatumu- will be limited to patients deemed inappropriate for mab plus chlorambucil versus chlorambucil for the first- fludarabine-based treatment. In addition to confirming line treatment of elderly or fragile patients with CLL who the clinical benefit of ofatumumab, a randomized confir- are unable to tolerate fludarabine-based chemotherapy matory trial will allow for a more accurate characteri- regimens. The study is designed to show a clinically mean- zation of adverse reactions caused by ofatumumab. ingful improvement in PFS. Regular FDA approval for the Characterization of infections was especially problematic treatment of patients with CLL has been based on a clini- because the background rate of severe and fatal infec- cally meaningful prolongation of PFS accompanied by an tions in heavily treated CLL patients is high (10). Be- acceptable safety profile. Superior PFS may represent a di- cause of the high background rate of infections in this rect clinical benefit if there is a large treatment effect and patient population and the absence of an internal con- the risks are acceptable.5 In hematologic malignancies, the trol, it was not possible to determine the additional risk clinical significance of a delay in disease progression is of infection posed by the administration of ofatumu- clearer because progression is generally associated with mab. However, ofatumumab-induced neutropenia may increased transfusion requirements and increased risk of increase the risk of life-threatening infections in this patient population.

Disclosure of Potential Conflicts of Interest 5 Guidance for Industry, Clinical Trail Endpoints for the Approval of Cancer Drugs and Biologics. Rockville (MD): U.S. Department of Health No potential conflicts of interest were disclosed. and Human Services, Food and Drug Administration; May 2007 [cited 2010 May 24]. Available from: http://www.fda.gov/downloads/Drugs/ Received 03/29/2010; revised 06/11/2010; accepted 06/14/2010; GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf. published OnlineFirst 07/02/2010.

References 1. Rai KR, Wasil T, Iqbal U, et al. Clinical staging and prognostic 7. Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute- markers in chronic lymphocytic leukemia. Hematol Oncol Clin North sponsored Working Group guidelines for chronic lymphocytic leuke- Am 2004;18:795–805, [vii]. mia: revised guidelines for diagnosis and treatment. Blood 1996;87: 2. Tam CS, O'Brien S, Lerner S, et al. The natural history of fludarabine- 4990–7. refractory chronic lymphocytic leukemia patients who fail alemtuzu- 8. Sirard C, Trehu EG. Hillmen trial of alemtuzumab in first-line chronic mab or have bulky lymphadenopathy. Leuk Lymphoma 2007;48: lymphocytic leukemia still provides valuable information. J Clin Oncol 1931–9. 2008;26:2411–2. 3. Pazdur R. Endpoints for assessing drug activity in clinical trials. 9. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis Oncologist 2008;13:19–21. and treatment of chronic lymphocytic leukemia: a report from the In- 4. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval ternational Workshop on Chronic Lymphocytic Leukemia updating summary: alemtuzumab as single-agent treatment for B-cell chronic the National Cancer Institute-Working Group 1996 guidelines. Blood lymphocytic leukemia. Oncologist 2008;13:167–74. 2008;111:5446–56. 5. Cephalon, Inc., Frazer (PA). Prescribing information Treanda (bend- 10. Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type amustine). February, 2010. of serious infections in fludarabine-refractory B-cell chronic lympho- 6. GlaxoSmithKline; Research Triangle Park (NC). Prescribing informa- cytic leukemia and small lymphocytic lymphoma: implications for tion. Arzerra (ofatumumab). October 2009. clinical trials in this patient population. Cancer 2002;94:2033–9.

4338 Clin Cancer Res; 16(17) September 1, 2010 Clinical Cancer Research

U.S. Food and Drug Administration Approval: Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab

Steven J. Lemery, Jenny Zhang, Mark D. Rothmann, et al.

Clin Cancer Res Published OnlineFirst July 2, 2010.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-10-0570

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/early/2010/08/20/1078-0432.CCR-10-0570. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.