Evaluation of Amivantamab Monotherapy and Combination Therapies in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
- Trial ID
- 2023-508418-40-00
- Protocol
- 61186372HNC2002
- Sponsor
- Janssen Cilag International
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **anti-tumor activity** of **amivantamab** in various treatment settings for participants with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Specifically, the study aims to assess the efficacy of amivantamab monotherapy in participants who have previously received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor, distinguishing between those who are HPV-unrelated (Cohort 1) and HPV-related (Cohort 4). Additionally, the study evaluates the combination of amivantamab with **pembrolizumab** (Cohort 2) or with pembrolizumab plus **carboplatin** (Cohort 5) in treatment-naïve participants in the R/M setting. For Cohort 3A, the study seeks to determine the recommended Phase 2 combination dose (RP2CD) of amivantamab with **paclitaxel** and to characterize the safety and **tolerability** of this combination in participants who have received PD-1/PD-L1 based therapy. Cohort 3B focuses on assessing the anti-tumor activity of amivantamab in combination with paclitaxel in a similar patient population. The clinical relevance of these objectives lies in the potential to improve therapeutic strategies and outcomes for patients with R/M HNSCC, a condition with limited treatment options and significant morbidity.
Participants
The clinical trial involves a total of **220 participants** diagnosed with **Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma**. The study population includes both male and female subjects, aged **18 years and older**, with no upper age limit specified. Participants were selected based on their prior treatment history, specifically those who have received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor, or are treatment-naïve in the recurrent/metastatic setting. The trial includes individuals with adequate organ and bone marrow function, and those with an **ECOG performance status** of 0 to 1. Participants' general health status is considered stable, with specific laboratory values required to be within normal limits. The trial does not specify particular lifestyle considerations such as diet or physical activity. The study population includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants. Key inclusion criteria focus on the participants' treatment history and current health status, ensuring they meet the necessary conditions for trial participation.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and tolerability of **amivantamab** in adult participants with recurrent/metastatic head and neck squamous cell carcinoma. This is a Phase 1b/2, open-label study, which involves multiple cohorts to assess the anti-tumor activity of amivantamab both as a monotherapy and in combination with standard care therapeutic agents. The trial is structured to include several cohorts, each with specific objectives, such as assessing the anti-tumor activity of amivantamab in combination with **pembrolizumab** and **carboplatin** in treatment-naïve participants, and determining the recommended Phase 2 combination dose of amivantamab with **paclitaxel**.
The trial is expected to commence recruitment on April 29, 2024, and is estimated to conclude by April 17, 2028. Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, laboratory values, and disease measurability according to RECIST v1.1. Following the screening, participants will attend regular follow-up visits to monitor treatment response and safety, with assessments including imaging and laboratory tests. The end-of-study visit will occur after the final treatment cycle to evaluate the overall outcomes and any long-term effects.
Participant involvement is anticipated to last throughout the trial duration, contingent upon continued eligibility and absence of conditions warranting early termination. Early termination may occur due to adverse events, disease progression, or withdrawal of consent. The trial employs a rigorous methodology to ensure the collection of reliable data, with endpoints including overall response rate and incidence of dose-limiting toxicities. The study's design and procedures are meticulously crafted to advance the understanding of amivantamab's therapeutic potential in this patient population.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Carboplatin Hikma** is provided as a 10 mg/mL concentrate for solution for infusion. It is administered via **intravenous use**. The product is manufactured by HIKMA FARMACÊUTICA (PORTUGAL), S.A. and is a chemical substance. The vials are labeled with a clinical label booklet, repackaged in the original commercial carton, and released for use in the clinical trial.
**JNJ-61186372**, containing the active substance **amivantamab**, is a solution for injection. It is administered via **subcutaneous use**. This product is developed by JANSSEN-CILAG INTERNATIONAL N.V. and is classified as a protein-based substance. The product is not a pediatric formulation and is used as a test medication in the trial.
**Carboplatin Kabi** is another 10 mg/mL concentrate for solution for infusion, similar to Carboplatin Hikma, and is administered via **intravenous use**. It is produced by FRESENIUS KABI DEUTSCHLAND GMBH and is also a chemical substance. The packaging and labeling process is consistent with the clinical trial requirements.
**KEYTRUDA**, with the active substance **pembrolizumab**, is provided as a 25 mg/mL concentrate for solution for infusion. It is administered via **intravenous use**. The product is manufactured by MERCK SHARP & DOHME B.V. and is a biological substance. The vials are labeled and repackaged for clinical trial use.
**CARBO-cell®** is a 10 mg/mL concentrate for solution for infusion, administered via **intravenous use**. It is produced by STADAPHARM GMBH and is a chemical substance. The product is prepared and labeled according to clinical trial standards.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Each medication is used in specific cohorts to assess its anti-tumor activity and safety profile in participants with recurrent/metastatic head and neck squamous cell carcinoma.
Efficacy
Efficacy in this clinical trial will be assessed using the primary endpoint of **Objective Response Rate (ORR)**, evaluated according to RECIST v1.1 criteria. This endpoint will be applicable to Cohorts 1, 2, 3B, and 5. For Cohort 3A, the primary endpoints include the incidence of Dose-Limiting Toxicities (DLTs) and the incidence and severity of Treatment-Emergent Adverse Events (TEAEs). The trial aims to evaluate the anti-tumor activity of **amivantamab** monotherapy and in combination with other therapeutic agents in participants with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
The efficacy parameters will be measured and collected at specified intervals throughout the study. The assessment of ORR will involve imaging studies to determine the size and progression of tumors, following the RECIST v1.1 guidelines. The schedule for these assessments will be aligned with the trial's protocol, ensuring consistent and accurate data collection. The analysis of these parameters will be conducted to determine the therapeutic impact of the investigational treatments on tumor response.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place, whichever is greater) at the time of informed consent.
- Cohorts 1 to 5: Have histologically or cytologically confirmed R/M HNSCC that is considered incurable by local therapies or for Cohort 6: have histologically or cytologically confirmed L/A HNSCC that is considered curable by surgery Cohort 1,2,3A, and 3B a. The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, or larynx. b. Any known p16 status of tumor must be negative. Note: All participants with an oropharyngeal tumor must have results of p16 status, per local testing. c. Participants must provide local testing results of PD-L1 status, if available. Cohort 4 d. Patients must have primary tumor location in oropharynx. Unknown primary tumors are not included. e. Primary tumor must be HPV-positive, confirmed by positive p16 test or highrisk HPV ISH in tissue (current or archival). f. Participants must provide local testing results of PD-L1 status, if available. Cohort 5: g. The eligible primary tumor location are the oropharynx, oral cavity, hypopharynx, or larynx. h. HPV status must be known (either positive or negative) for patients with primary tumor location in oropharynx with p16 test or high-risk HPV ISH in tissue. i. Participants must provide local testing results of PD-L1 status. Cohort 6: j. The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, or larynx. k. Any known p16 status of tumor must be negative. Note: All participants with an oropharyngeal tumor must have results of p16 status, per local testing. Participants must provide local testing results of PD-L1 status. l. Participants must have Stage III or IVa disease (American Joint Committee on Cancer Staging Manual, 8th edition). Participants must have resectable disease.
- Participants must meet the following cohort-specific requirements: Cohort 3A: Dose Confirmation Cohort a. Have evaluable disease (defined as having at least 1 non-target lesion according to RECIST v1.1). If only 1 evaluable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed ≥7 days after the biopsy. Tumor lesions situated in a previously irradiated area are considered evaluable if progression following radiation has been demonstrated in such lesions. Cohorts 1, 3B and 4: Dose Expansion Cohorts b. Have measurable disease according to RECIST v1.1. If only 1 measurable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed ≥7 days after the biopsy. Tumor lesions situated in a previously irradiated area are considered measurable if progression following radiation has been demonstrated in such lesions. A lesion that was biopsied during Screening should only be assessed as a target lesion if a post-biopsy imaging is performed >7 days and confirms that it still meets measurability criteria and is amenable to accurate and reproducible measurement. Cohorts 2 and 5: Dose Expansion Cohorts c. Have measurable disease according to RECIST v1.1. If only 1 measurable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed ≥7 days after the biopsy. Tumor lesions situated in a previously irradiated area are considered measurable if progression following radiation has been demonstrated in such lesions. Cohort 6: d. Have evaluable disease (defined as having at least 1 non-target lesion according to RECIST v1.1). If only 1 evaluable lesion exists, it may be used for the screening biopsy as long as baseline tumor assessment scans are performed ≥7 days after the biopsy.
- If available, provide adequate tumor tissue for a baseline sample following the most recent systemic anticancer therapy. The tissue sample should meet the sample requirements as outlined in the lab manual and should be accompanied with pathology report to review tumor specifications. In addition, participants must meet the following cohort-specific requirements: Cohorts 1, 3A, 3B and 4: Dose Confirmation and Expansion Cohorts a. The sponsor reserves the right to allocate the final enrollment slots in Cohorts 1 and 3B to ensure that at least 30 participants in Cohort 1 expansion (including at least 10 participants enrolled before the expansion Cohort 1 via Amendment 2), at least 10 participants in Cohorts 3A and 3B combined, and at least 10 participants in Cohort 4 provide adequate tumor tissue, either based on acceptable archival specimen or a screening biopsy. If a different dose level is used in Cohorts 3A and 3B, tumor tissue samples are required for at least 10 participants in Cohort 3B. Cohorts 2 and 5: Dose Expansion Cohorts b. If no adequate tumor tissue is available for a baseline sample, the participant must consent to a screening biopsy. If no adequate tumor tissue is available and a screening biopsy is not clinically feasible or prohibited per local regulations, the participant is not eligible. Cohort 6: c. If no adequate tumor tissue is available for a baseline sample, the participant must consent to a screening biopsy. If no adequate tumor tissue is available and a screening biopsy is not clinically feasible or prohibited per local regulations, the participant is not eligible.
- Participant may have a prior or concurrent second malignancy (other than the disease under study) which natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s). Prior or concurrent second malignancies must be reviewed and agreed to with the medical monitor.
- Cohorts 1, 2, 3A, 3B, 4, and 5 only: Toxicities from previous anticancer therapies should have resolved to baseline levels or to Grade 1 or less prior to the first dose of study treatment (except for alopecia or post-radiation skin changes [any grade], Grade ≤2 peripheral neuropathy and Grade ≤2 hypothyroidism stable on hormone replacement).
- Must meet the following cohort-specific requirements: (1/2) Cohort 1 and 4: Amivantamab Monotherapy a. Participant must have progressed on or after treatment for R/M disease with platinum-based chemotherapy and a PD-1/PD-L1 inhibitor (in combination or as separate lines) or have documented intolerance to these treatments. If 1 or both of these treatments were given for locally advanced disease with progression within 6 months, this may count as treatment for R/M disease. b. Participant must have progressed on most recent line for R/M disease. Maximum of 2 prior lines of systemic therapy in the R/M setting. c. Participant must have not previously received anti-EGFR therapy (inclusive of TKIs and antibodies). Cohort 2: Pembrolizumab + Amivantamab and Cohort 5: Pembrolizumab + Amivantamab + Carboplatin d. Participant must be treatment-naïve in the R/M setting. Systemic therapy which was completed more than 6 months prior to first study treatment administration, if given as part of treatment for locally advanced disease with curative intent, is allowed except for anti-EGFR or anti-PD-1/PD-L1 therapy. e. Participant must have not had disease progression within 6 months of completion of curatively intended treatment for locally advanced disease. f. Participants must have documented local testing results demonstrating a PD-L1 CPS ≥1 (using a 22C3 antibody test) within 3 months of the first dose of study treatment for Cohort 2 or within 6 months of the first dose of study treatment for Cochort 5. Local testing must be performed in accordance with local guidelines using an FDA-approved or other validated test in a CAP/CLIA certified laboratory (sites in the United States) or an accredited local laboratory (sites outside of the United States) in accordance with site SoC. In the European Union, the local test must be CE Marked or an in-house test from health institutions in the European Union in accordance with Article 5(5) of the IVDR 2071/746, as amended. Note that a copy of the test report documenting the PD-L1 must be included in the participant records.
- Must meet the following cohort-specific requirements: (2/2) Cohorts 3A and 3B: Paclitaxel + Amivantamab g. Participant must have progressed on or after treatment for R/M disease with PD-1/PD-L1 based therapy either as a monotherapy or as combination with platinum-based chemotherapy or have documented intolerance to this treatment. If this treatment was given for locally advanced disease with progression within 6 months, this may count as treatment for R/M disease. h. Participant must have progressed on most recent line for R/M disease. Maximum of 2 lines of systemic therapy in the R/M setting. i. Participant must have not previously received anti-EGFR therapy (inclusive of TKIs and antibodies) or taxane. Cohort 6: j. Participants must be treatment naïve. k. Participants must have documented local testing results demonstrating a PD-L1 CPS ≥1 (using a 22C3 antibody test) within 3 months of the first dose of study treatment. Local testing must be performed in accordance with local guidelines using an FDA-approved or other validated test in a CAP/CLIA-certified laboratory (sites in the US) or an accredited local laboratory (sites outside of the US) in accordance with site SoC. In the EU, the local test must be CE-marked or an in-house test from health institutions in the EU in accordance with Article 5(5) of the IVDR 2071/746, as amended. Note that a copy of the test report documenting the PD-L1 must be included in the participant records.
- Have an ECOG performance status of 0 to 1
- Have at least 1 of the following: a. Serum creatinine ≤1.5×ULN b. Estimated glomerular filtration rate ≥45 mL/min, based on the MDRD 4-variable formula
- Participants are eligible if they have the following lab values: a. AST ≤3 x ULN (≤5 x ULN if liver metastases are present) b. ALT ≤3 x ULN (≤5 x ULN if liver metastases are present) c. Total bilirubin ≤1.5x ULN, participants with congenital nonhemolytic hyperbilirubinemia such as Gilbert’s syndrome can enroll if conjugated bilirubin is within normal limits. d. For Cohort 6 only: albumin ≥3.0 g/dL
- Participant must have adequate organ and bone marrow function as follows, without history of red blood cell transfusion, platelet transfusion, or use of granulocyte colony-stimulating factor within 7 days prior to the date of the laboratory test. Participants should have: a. Hemoglobin ≥9g/dL. b. Neutrophils ≥1.5 x 103/μL. c. Platelets ≥100 x 103/μL.
- Participants must meet the following cohort-specific requirements: Cohort 2, Cohort 5, and Cohort 6 (ie, cohorts receiving pembrolizumab): Thyroid function laboratory values within the normal range. Thyroid function laboratory values within the normal range.
Exclusion Criteria
- Uncontrolled illness, including but not limited to (applicable to all participants): a. Diabetes. b. Ongoing or active infection (includes infection requiring treatment with antimicrobial therapy [participants will be required to complete antibiotics 1 week prior to starting study treatment]) or diagnosed or suspected viral infection. c. Active bleeding diathesis. d. Impaired oxygenation requiring continuous oxygen supplementation. e. Psychiatric illness/social situation that would limit compliance with study requirements. Cohort2, Cohort 5, and Cohort 6 (ie, cohorts receiving pembrolizumab): f. Autoimmune disease that has required systemic therapy in past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic therapy. g. History of Grade 3 or higher immune-related AEs from prior anticancer therapy or a monoclonal antibody, except for endocrinopathies that are stable on replacement therapies. h. Participant had an allogeneic tissue/solid organ transplant.
- Medical history of (non-infectious) ILD/pneumonitis/pulmonary fibrosis, or has current ILD/pneumonitis, or where suspected ILD/pneumonitis/pulmonary fibrosis cannot be ruled out by imaging at screening.
- Known allergies, hypersensitivity, or intolerance to excipients of amivantamab or rHuPH20 (refer to the IB). Cohort2, Cohort 5, and Cohort 6 (ie, cohorts receiving pembrolizumab): Known allergies, hypersensitivity, intolerance, or contraindication to excipients of pembrolizumab (refer to the product label). Cohorts 3A and 3B: Paclitaxel + Amivantamab Known allergies, hypersensitivity, intolerance, or contraindication to excipients of paclitaxel (refer to the product label). Cohort 5: Pembrolizumab + Amivantamab + Carboplatin - known allergies, hypersensitivity, intolerance, or contraindication to excipients of carboplatin (refer to the product label)
- Participant has a history of clinically significant cardiovascular disease including, but not limited to the following: Diagnosis of deep vein thrombosis or pulmonary embolism within 8 weeks prior to the first dose of study treatment or any of the following within 6 months prior to the first dose of study treatment: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary/peripheral artery bypass graft, or any acute coronary syndrome. Clinically non-significant thrombosis, such as non-obstructive catheter-associated clots, are not exclusionary. Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (eg, placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate). Uncontrolled (persistent) hypertension: systolic blood pressure >180 mm Hg; diastolic blood pressure >100 mm Hg. Congestive heart failure defined as NYHA Class III, IV or Hospitalization for congestive heart failure (any NYHA Class) within 6 months of the first dose of study treatment. Pericarditis/clinically significant pericardial effusion. Myocarditis.
- Participant has, or will have, any of the following: a. An invasive operative procedure with entry into a body cavity, within 4 weeks or without complete recovery before the first administration of study treatment. Thoracentesis, if needed, and percutaneous biopsy for baseline tumor tissue sample may be done less than 4 weeks prior to the first administration of study treatment, as long as the participant has adequately recovered from the procedure prior to the first dose of study treatment in the clinical judgement of the investigator. b. Significant traumatic injury within 3 weeks before the start of the first administration of study treatment (all wounds must be fully healed prior to Day 1). c. Expected major surgery while the investigational agent is being administered or within 6 months after the last dose of study treatment.
- Participant with untreated brain metastases
- Participant has a medical history or known presence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation.
- HIV-positive participants are not eligible if they meet any of the following: a. Detectable viral load (ie, >50 copies/mL) at screening. b. CD4+ count <300 cells/mm3 at screening. c. AIDS-defining opportunistic infection within 6 months of screening. d. Not receiving HAART. Any changes in HAART due to resistance/progression should occur at least 3 months prior to screening. A change in HAART due to toxicity is allowed up to 4 weeks prior to screening.
- Received prior chemotherapy, targeted cancer therapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or 4 half-lives, whichever is longer, before the first administration of study treatment. The maximum required washout is 28 days.
- Received radiotherapy for palliative purposes within 7 days of the first administration of study treatment.
- Requires a prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study;
- Received an investigational treatment (including investigational vaccines, but not including anticancer therapy) or used an invasive investigational medical device within 6 weeks before the planned first dose of study treatment.
- Cohort 2,Cohort 5, and Cohort 6 (ie, cohorts receiving pembrolizumab): Prohibited immunosuppressive medication use within 7 days prior to the first administration of study treatment.
- 14.Cohort 2,Cohort 5, and Cohort 6 (ie, cohorts receiving pembrolizumab): Participant has received a live or live attenuated vaccine within 30 days prior to the first dose of study drug. Vaccines approved or authorized for emergency use (eg, COVID-19) and non-live vaccines (eg, influenza) are allowed.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 29 Apr 2024 | 19 |
 Germany | Recruiting | 29 Apr 2024 | 11 |
 Poland | Recruiting | 29 Apr 2024 | 10 |
 Spain | Recruiting | 29 Apr 2024 | 15 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Carboplatin Hikma 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | — | — | PRD808124 |
CARBO-cell® 10 mg/ml Infusionslösung, Konzentrat zur Herstellung einer Infusionslösung | Test | INFUSIONSLÖSUNG, KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | — | — | PRD1972920 |
JNJ-61186372 | Test | SOLUTION FOR INJECTION | SUBCUTANEOUS USE | — | — | PRD11078981 |
Carboplatin Kabi 10 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Test | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | INTRAVENOUS USE | — | — | PRD11854707 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENUS USE | — | — | PRD12081132 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD4323105 |