A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent Or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048)

A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048)

SECONDARY IDENTIFICATION NUMBER

MK-3475-048, KEYNOTE-048; ClinicalTrials.gov: NCT02358031

FDA CLINICAL TRIAL REFERENCE (CTR) NUMBER

2015-CT0283

SCIENTIFIC TITLE

A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

PROJECT DESCRIPTION

Participants with recurrent or metastatic (R/M) squamous cell cancer of the head and neck (HNSCC) will be randomly assigned to receive pembrolizumab alone, or pembrolizumab + a platinum-based drug (cisplatin or carboplatin) + 5-Fluorouracil (5-FU), or cetuximab + a platinum- based drug (cisplatin or carboplatin) + 5-FU. The primary study hypothesis is that pembrolizumab or pembrolizumab in combination with chemotherapy prolongs progression free survival and overall survival compared to standard treatment.

NUHRA DETAILS

Regime Classification Priority 2010 - 2016 Health Technology Development Drug Discovery and Development

PROJECT DURATION

Start Date Duration in Months Target Completion Date Actual Completion Date 2015-08-10 58 2020-06-10 0000-00-00

PROJECT STATUS

Ongoing

REASON FOR PROJECT PENDING/SUSPENSION/TERMINATION

Unspecified

IMPLEMENTING AGENCY (PRIMARY SPONSOR)

Institution Classification Region LTO # Merck Sharp & Dohme (I.A.) LLC Private Business NCR 3000006624320

COOPERATING AGENCY (SECONDARY SPONSOR)

Institution Classification Region LTO # No records Found.

CONTRACT RESEARCH ORGANIZATION (CRO) INFORMATION

Institution Classification Region LTO # No records Found.

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 1/7 FUNDING AGENCY (SOURCES OF MONETARY OR MATERIAL SUPPORT)

Institution Amount Region Merck Sharp & Dohme (I.A.) LLC P 99,090,973.00 NCR

CONTACT FOR PUBLIC QUERIES

Name E-Mail Phone Number Institution and Institution Address Priscila Perez [email protected] +632 87849587 / +63 917 811 80 26/F Philamlife Tower Paseo De 93 Roxas Makati City

CONTACT FOR SCIENTIFIC QUERIES

Name E-Mail Phone Number Institution and Institution Address Priscila Perez [email protected] +632 87849587 / +63 917 811 80 26/F Philamlife Tower Paseo De 93 Roxas Makati City

IMPLEMENTING AGENCY (PRIMARY SPONSOR)

Name Expertise Affiliation Ellie May Villegas, MD Principal Investigator Perpetual Succour Hospital Eugenio Emmanuel Regala, MD Principal Investigator The Medical City John P. Querol, MD Principal Investigator Veterans Memorial Medical Center Maria Belen E. Tamayo, MD Principal Investigator Makati Medical Center Priscilla B. Caguioa, MD Principal Investigator St. Luke's Medical Center - Quezon City

RESEARCH CLASSIFICATION

Clinical Trial

HEALTH CONDITION(S) OR PROBLEM(S) STUDIED

Recurrent Head and Neck CancerMetastatic Head and Neck Cancer

PRIMARY OUTCOMES

•Progression Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR) in Participants With Programmed Cell Death Ligand 1 (PDL1)-Positive Expression [ Time Frame: Up to 3 Years ]•Overall Survival in Participants With PDL1-Postive Expression [ Time Frame: Up to 5 Years ]•PFS per RECIST 1.1 by BICR in All Participants [ Time Frame: Up to 3 Years ]•Overall Survival in All Participants [ Time Frame: Up to 5 Years ]

KEY SECONDARY OUTCOMES

•PFS at 6 Months per RECIST 1.1 by BICR [ Time Frame: Up to 6 Months ]•Objective Response Rate per RECIST 1.1 by BICR [ Time Frame: Up to 3 Years ]•PFS at 12 Months per RECIST 1.1 by BICR [ Time Frame: Up to 12 Months ]•Time to Deterioration in Quality of Life Global Health Status/Quality of Life Scales of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 Score for Items 29 and 30 [ Time Frame: Up to 3 Years ]

RECRUITMENT STATUS

Completed

COUNTRIES OF RECRUITMENT

Argentina, Australia, Austria, Brazil, Canada, Chile, Colombia, Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Latvia, Malaysia, Mexico, Netherlands, Norway, Peru, Philippines, Poland, Russia, Singapore, South Africa, Spain,

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 2/7 Sweden, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States

FDA DOCUMENT TRACKING NUMBER

20150204161623, 20150508155056, 20150918160908, 20160831151846, 20170324164513, 20170831143412, 20171211091138, 20190124175217

FDA APPROVAL DATE

2015-04-22

ERC APPROVAL DATE

0000-00-00

FIRST ENROLMENT DATE

2015-08-10

TARGET SAMPLE SIZE (PHILIPPINES)

ACTUAL SAMPLE SIZE (PHILIPPINES)

REASON FOR THE DIFFERENCE BETWEEN TARGET & ACTUAL SAMPLE SIZES

Screening was closed last 22Dec2016. There were 17 screen failures out of 37 screened from 10Aug2015 to 12Nov2016.

DATE OF FIRST ENROLMENT

2015-08-10

KEY INCLUSION AND EXLUSION CRITERIA (CT)

Inclusion Criteria: Histologically- or cytologically-confirmed recurrent or metastatic head and neck squamous cell carcinoma considered incurable by local therapies •No prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months prior if given as part of multimodal treatment for locally advanced disease) •Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology) •Measurable disease •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 •Adequate organ function •Can provide tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient): A newly obtained biopsy (within 90 days prior to start of study treatment) is preferred but an archival sample is acceptable. •Have results from testing of HPV status for oropharyngeal cancer •Female participants of childbearing potential should have a negative pregnancy test and must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication •Male participants must agree to use an adequate method of contraception starting with the first dose of study medication through 180 days after the last dose of study medication

Exclusion Criteria: •Disease suitable for local therapy administered with curative intent •Has progressive disease (PD) within six (6) months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC •Radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or not fully recovered from adverse events due to a previously administered treatment •Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks of the first dose of study medication

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 3/7 •Life expectancy of 3 months and/or has rapidly progressing disease •Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication (physiologic doses of corticosteroids may be approved after consultation with the Sponsor)

•Diagnosed and/or treated additional malignancy within 5 years prior to randomization with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers

•Has had an allogeneic tissue/solid organ transplant •Active central nervous system metastases and/or carcinomatous meningitis •Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment •History of (non-infectious) pneumonitis that required steroids or current pneumonitis •Active infection requiring systemic therapy •Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial •Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study medication •Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or previously participated in Merck MK-3475 clinical trial •Known history of human immunodeficiency virus (HIV) •Known active Hepatitis B or C •Received a live vaccine within 30 days of planned start of study medication

STUDY TYPE

Interventional

INTERVENTION NAME

Biological: Pembrolizumab Other Name: KEYTRUDA® MK-3475; Drug: Cisplatin; Drug: Carboplatin; Drug: 5-FU; Biological: Cetuximab

INTERVENTION DESCRIPTION

Experimental: Pembrolizumab Participants receive pembrolizumab 200 mg, intravenously (IV) on Day 1 of each week in 3-week cycles for up to 24 months. Intervention: Biological: Pembrolizumab • Experimental: Pembrolizumab + Platinum + 5-FU Participants receive pembrolizumab 200 mg, intravenously (IV) on Day 1 of each week in 3-week cycles for up to 24 months; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV(Investigator's choice) on Day1 of each week in 3-week cycles (6 cycle maximum); plus 5-FU 1000 mg/m^2/day IV continuous from Day1-4 of each 3- week cycle (6 cycle maximum). Interventions: ○ Biological: Pembrolizumab ○Drug: Cisplatin ○ Drug: Carboplatin ○ Drug: 5-FU • Active Comparator: Cetuximab + Platinum + 5FU Participants receive cetuximab on Day 1 at a dose of 400 mg/m^2 IV, and then 250 mg/m^2 IV on Day 1 of each week until disease progression or unacceptable toxicity; plus cisplatin 100 mg/m^2 IV or carboplatin AUC 5 IV (Investigator's choice) on Day 1 of each week in 3-week cycles (6 cycle maximum for platinum-based therapy); plus 5-FU 1000 mg/m^2/day IV continuous from Day 1-4 of each 3-week cycle (6 cycle maximum). Interventions: ○ Drug: Cisplatin ○ Drug: Carboplatin ○ Drug: 5-FU ○ Biological: Cetuximab

AMENDMENT APPROVAL DATE/REASONS

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 4/7 Classification Approval Date Reason 2016-10-28 Amendments related to the protocol 1. Sections 1 and 2.1, Trial Summary and Trial Design: Enrollment target updated from 780 to 825 subjects. Overall survival (OS) has been added as a co-primary endpoint and the biomarker strategy for KN048 has been updated.4. Section 2.1 Trial Design: Removed description of the strongly positive PD-L1 enrichment population. Study will now recruit all PD-L1 expression levels with no enriched population. 7. Section 3.2, 3.3, Secondary Objective(s) & Hypothesis(es), Exploratory Objectives: 2017-05-19 Amendments related to the protocol Primary Reasons for the amendment 048-07: 1. Sections 3.1, 4.1.3, 8.1.3, 8.2.5, 8.2.6, 8.2.7, 8.2.8: References to PD-L1 10% Combined Positive Score (CPS) were removed. Hypothesis numbering was modified accordingly. CPS 10% will no longer be included in the analyses. Only the 20% and 1% CPS cutpoints will be analyzed. 2017-10-20 Amendments related to the protocol 2018-01-12 Amendments related to the protocol 2019-03-20 Amendments related to the protocol Primary Reasons for the amendment 048-10 dated 11Jan2019: 1. Sections 8.1.3, 8.1.4.2, 8.2.7, 8.2.9.2, Power and Sample Size, Efficacy Interim Analyses, Sample Size and Power Calculation, Efficacy Interim Analyses: Edits were made to Table 17 and Table 23 to indicate the number of expected events, rather than required events. References to “event-driven” were removed. Text was modified to describe the timing of the final analysis to account for the scenario if the number of deaths for one hypothesis accumulates slower than expected. Rationale of Change: To prevent the trial from continuing to an unreasonable duration for the final analysis. ADDITIONAL CHANGE(S) FOR THIS AMENDMENT: 1. Section 2.1, Trial Design: Corrected language to indicate that interim PFS/OS analyses are time-driven, rather than event-driven. Updated to be consistent with Section 8. 2. Section 4.2.2, Rationale for Dose Selection/Regimen/Modification: Corrected the following text to indicate pembrolizumab dosing is Q3W: Five studies compared 2 mg/kg Q3W vs. 10 mg/kg Q3W (corrected from Q2W to Q3W). Updated to correct the dose frequency of the 10 mg/kg dose. 3. Section 4.2.3.1.2, Secondary (Rationale for Endpoints): Removed DOR from statement to indicate only ORR is a secondary endpoint. Updated to be consistent with other sections of the protocol. 4. Section 5.2.1.2.1, Dose Modification for Pembrolizumab, Table 4: Solid organ transplant rejection (SOTR) was deleted from Grade 3, All Other Immune-related AEs, as an event that

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 5/7 Classification Approval Date Reason requires discontinuation. Text updated to align with current pembrolizumab standard protocol template. 5. Section 6.2 Second Course Phase – Retreatment with Pembrolizumab: An arrow was added to the Survival Status row to indicate that it is assessed throughout treatment and follow-up during the study, to align with Section 6.1.1 and Section 6.1.2. Footnote c was added to this row. Correction of typographical omission. 6. Section 7.1.5.3.2, Follow-up Visits: Language was added to allow a less- frequent imaging schedule with Sponsor approval. To allow flexibility in imaging frequency for subjects who stopped treatment with pembrolizumab due to CR or who completed the scheduled pembrolizumab treatment period, and to align with pembrolizumab program standards. 7. Section 7.2.1, Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor: An error in the spelling of cetuximab was corrected. Correction of typographical error. 8. Section 7.2.3.2, Events of Clinical Interest: The list of ECIs for the trial was corrected to remove Item 3, additional adverse events. Corrected to align with edits made in Amendment 09. 9. Section 8.2.5.2, Statistical Methods for Safety Analyses: Table 21 was modified to eliminate Tier 1 from the analysis strategy description. Deleted to align with edits made in sSAP since no Tier 1 events are in the trial. 10. Section 8.2.9.2, Efficacy Interim Analyses: Table 23 was corrected. Under IA2 and Final Analysis sections of the table, “OS superiority mono/combo vs. SOC in subjects with PD-L1 CPS 20 (H10/H14)” was modified to read “OS superiority mono/combo vs. SOC in all subjects H10/H14)”. Correction of an error in Amendment 09. Text was added to describe PFS analyses; the Lan and DeMets (1989) calendar time method will be used for alpha-spending to generate the group-sequential design. The updated bounds for the PFS hypotheses were added in Table 24. This was added to the sSAP prior to IA1 to account for the scenario if events accumulate faster than expected.

METHOD OF ALLOCATION

Randomized

MASKING / BLINDING

Open Label

MASKING DETAILS

Unspecified

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 6/7 ASSIGNMENT

Parallel

PURPOSE

Treatment

PHASE

Phase III

RESEARCH UTILIZATION

Utilization Utilization Info Publication Oral Presentation Drug Literature Posters Others For updates, please refer to ClinicalTrials.gov data:https://www.clinicalt rials.gov/ct2/show/record/NCT02358031?term=NCT02358031&rank=1

Contact #s.: (+632) 8377534, (+632) 8377537, (+632) 8372071-80 loc. 2117, 2112 Saliksik Building, DOST Compound, Gen. Santos Ave., Bicutan Taguig City 1631 Philippines Page 7/7