IRB Study Number 25-958
Status Recruiting
Phase Phase 3
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
This is a Phase 3, open-label, randomized, multicenter study to compare petosemtamab plus pembrolizumab vs pembrolizumab alone in the 1L treatment of PD-L1+ (CPS≥1) metastatic/recurrent HNSCC disease that is not amenable to curative therapy. Approximately 600 participants with incurable recurrent or metastatic HNSCC who are eligible to receive pembrolizumab as 1L monotherapy will be randomized 1:1 to the following 2 treatment arms: (1) petosemtamab 1500 mg Q2W in combination with pembrolizumab 400 mg Q6W (investigational arm) or (2) pembrolizumab 400 mg Q6W alone (control arm).
Primary Objectives:
- To compare overall survival (OS) in first-line incurable metastatic/recurrent PD-L1+ (CPS ≥1) HNSCC treated with:
-Petosemtamab + pembrolizumab vs
-Pembrolizumab alone - To compare objective/overall response rate (ORR) per RECIST v1.1, as assessed by blinded independent central review (BICR) between the two treatment arms.
Secondary Objectives:
- To evaluate antitumor activity measured by progression-free survival (PFS) per RECIST v1.1, assessed by BICR.
- To evaluate antitumor activity measured by duration of response (DOR) per RECIST v1.1, assessed by BICR.
Exploratory Objectives:
- Explore tumor and blood biomarkers predictive of response or resistance to therapy. Candidate biomarkers include, but are not limited to:
-EGFR expression
-LGR5 expression
-ctDNA (including EGFR amplification)
-PD‑L1 expression (CPS <20 vs ≥20) - Explore and develop diagnostics that may support registration of petosemtamab in combination with pembrolizumab.
Inclusion Criteria
- Signed ICF before initiation of any study-specific procedures
- Age ≥ 18 years at signing of ICF
- Histologically confirmed HNSCC with evidence of metastatic or locally recurrent disease not amenable to local therapy with curative intent. Participants with HNSCC primary tumor locations in oropharynx, oral cavity, hypopharynx, and larynx are eligible.
- HNSCC participants eligible to receive pembrolizumab as 1L monotherapy with tumors expressing PD-L1, CPS ≥1, as determined by an IHC test in a central laboratory.
- HNSCC participants should not have had previous systemic therapy administered in the incurable recurrent or metastatic setting, although previous systemic therapy as part of multimodal treatment for locally advanced disease is allowed if PD was ≥6 months after the last platinum containing- therapy dose. Previous treatments with anti PD-(L)1 or anti-EGFR therapies are not allowed. In the case of cetuximab, participants who have received cetuximab with radiotherapy as a local treatment and PD was >1 year after the last dose of cetuximab are eligible.
- A new tumor biopsy (preferred) or archived tumor tissue to enable determination by central laboratory of PD-L1 status (and p16 status for oropharynx primaries.
- Measurable disease per Investigator assessment as defined by RECIST v1.1 by radiologic methods
- ECOG PS of 0 or 1
- Life expectancy ≥ 12 weeks, as per Investigator assessment
- Left ventricular ejection fraction (LVEF) ≥50% or ≥institutional normal limit, whichever is higher, by ECHO or multigated acquisition (MUGA) scan
- Adequate organ function:
a) Absolute neutrophil count (ANC) ≥1.5 X 109/L
b) Hemoglobin ≥9 g/dL; red blood cell (RBC) transfusion is permitted to meet criteria, if there is no suspicion of active bleeding or hemolysis
c) Platelets ≥100 x 109/L
d) Serum magnesium and corrected calcium ≤Grade 1.
e) Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤2.5 x upper limit of normal (ULN); in cases of liver metastases, ALT/AST ≤5 x ULN, but in both situations, the bilirubin levels are required to be ≤1.5 x ULN, unless due to known Gilbert’s syndrome when total bilirubin ≤3.0 x ULN or direct bilirubin ≤1.5 x ULN will be allowed.
f) Serum creatinine ≤1.5 x ULN or creatinine clearance ≥60 mL/min calculated according to the Cockroft and Gault formula
g) Serum albumin ≥3 g/dL
h) International Normalized Ratio (INR) ≤1.5xULN, unless participant is receiving anticoagulant therapy, in which case INR is not greater than the upper limit of the therapeutic range of intended used anticoagulant. Prothrombin time (PT) may be used instead of INR (PT ≤1.5xULN, unless participant is receiving anticoagulant therapy, in which case PT is not greater than the upper limit of the therapeutic range of intended used anticoagulant). - Activated partial thromboplastin time (APTT) or partial thromboplastin time (PTT) ≤1.5xULN, unless participant is receiving anticoagulant therapy and APTT or PTT is not greater than the upper limit of the therapeutic range of intended used anticoagulant.
Human immunodeficiency virus (HIV)-positive participants are eligible only if the cluster of differentiation 4 (CD4+) count is ≥ 300/μL, viral load is undetectable, and the participant is currently receiving highly active antiretroviral therapy (HAART). Note: Screening test for HIV is not required unless there is clinical suspicion or testing is mandated by local health authorities for study participation. Participants with a history of HIV are required to complete CD4 and viral load testing.
Exclusion Criteria
The presence of any of the following criteria excludes a participant from participating in the study:
- CNS metastases that are untreated or already treated but symptomatic, or require radiation, surgery, or continued steroid therapy to control symptoms within 21 days prior to randomization
- Known leptomeningeal involvement
- Any systemic anticancer therapy or investigational drug (including those with indications other than anticancer therapy) within 4 weeks or 5 half-lives (if known), whichever is shorter, before randomization
- Requirement for immunosuppressive medication (eg, methotrexate, cyclophosphamide)
- Major surgery or radiotherapy within 3 weeks of randomization
- Clinically significant toxicities related to prior anticancer therapy that has not returned to ≤ Grade 1 or baseline except for ≤Grade 2 myalgia, neuropathy, alopecia, and any prior therapy-related endocrinopathies.
- History of hypersensitivity reaction to any of the excipients of petosemtamab or pembrolizumab required for this study
- Unstable angina; history of congestive heart failure of Class II-IV New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (except appropriately treated atrial fibrillation, paroxysmal supraventricular tachycardia); or history of myocardial infarction within 6 months prior to randomization
- History of prior malignancies within the last 5 years, with the exception of excised local cancer (e.g., cervical intraepithelial neoplasia, non-melanoma skin cancers)
- Current dyspnea at rest of any origin, or other diseases requiring continuous oxygen therapy. Participants with a history of non-infectious pneumonitis/interstitial lung disease (ILD) or evidence of current pneumonitis/ILD on baseline chest imaging will be excluded
- Current serious illness or medical conditions including, but not limited to, uncontrolled active infection, clinically significant pulmonary, metabolic, or psychiatric disorders that preclude safety and efficacy evaluation, or unwillingness or inability to comply with procedures required in either arm of this protocol.
- Participants with known infectious diseases:
a) Active hepatitis B infection (hepatitis B surface antigen [HBsAg] positive) without receiving antiviral treatment. Note: • Participants who are HBsAg positive must receive antiviral treatment (e.g., lamivudine, tenofovir, entecavir, or other antiviral agents), starting ≥7 days before randomization.
-Participants with antecedents of hepatitis B (ie, anti-hepatitis B core [HBc] positive, HBsAg and hepatitis B virus [HBV]- deoxyribonucleic acid [DNA] negative) are eligible.
b) Known positive test for hepatitis C virus (HCV) ribonucleic acid (RNA). Note: Participants in whom HCV infection resolved spontaneously (ie, positive HCV antibodies without detectable HCV RNA) or who achieved a sustained response after antiviral treatment and show absence of detectable HCV RNA ≥6 months (with the use of interferon [IFN]-free regimens) or ≥12 months (with the use of IFN-based regimens) after cessation of antiviral treatment are eligible.
Note: testing for HBV and HCV is not required unless there is a known history or clinical suspicion of infection or testing is mandated by local health authorities for study participation. - Pregnant or breastfeeding participants; participants of childbearing potential must use highly effective contraception methods per local standards prior to study entry, for the duration of study participation, and for 6 months after the last dose of petosemtamab or 4 months after the last dose of pembrolizumab, whichever is longer. Fertile male participants must use highly effective contraception methods per local standards with their partners for the duration of study participation, and for 6 months after the last dose of petosemtamab or 4 months after the last dose of pembrolizumab, whichever is longer (see Section 14.9.1).
- The participant has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy of prednisone >10 mg/day or equivalent, or any other form of immunosuppressive therapy. Corticosteroids used as premedication for IRRs before C1D1 as specified in the protocol are allowed (see Section 6.1.4.3).
- The participant has an active autoimmune disease that has required systemic immune suppressive treatment in the past 2 years; replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered immune suppressive treatment.
- The participant has had an allogeneic tissue/solid organ transplant
- The participant has a primary tumor site of nasopharynx, or sinonasal carcinoma (any histology)
