Prospective registration

Phase 1b/2, Open-label Study of Amivantamab Monotherapy and Amivantamab in Addition to Standard of Care Therapeutic Agents in Participants with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Phase 1b/2, Open-label Study of Amivantamab Monotherapy and Amivantamab in Addition to Standard of Care Therapeutic Agents in Participants with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Qin Xie 

Guo Ye 

Building A, Xinyan Mansion, No.65 Guiqing Road, Xuhui District,Shanghai 200233,P.R.China

150 Jimo Road, Pudong New Area, Shangha

Johnson & Johnson (China) Investment Ltd.

Shanghai East Hospital

Yes

Ethics Committee of Drug/Device Clinical Trial, Shanghai East Hospital

Siwei Bao

150 Jimo Road, Pudong New Area, Shangha

Shanghai East Hospital

150 Jimo Road, Pudong New Area, Shangha

Johnson & Johnson (China) Investment Ltd.

Squamous cell carcinoma of the head and neck

Interventional study

2

Non randomized control 

The primary objectives of this study are to determine RP2CD(s) and evaluate safety and tolerability of amivantamab in addition to paclitaxel, and to assess anti-tumor activity of amivantamab monotherapy and in addition to pembrolizumab, paclitaxel, or pembrolizumab + carboplatin. Secondary objectives will further evaluate safety and other measures of efficacy.

1.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. 2.Have histologically or cytologically confirmed R/M HNSCC that is considered incurable by local therapies. Cohorts 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 a. Patients must have primary tumor location in oropharynx. Unknown primary tumors are not included. b. Primary tumor must be HPV-positive, confirmed by positive p16 test or highrisk HPV ISH in tissue (current or archival). c. Participants must provide local testing results of PD-L1 status, if available; 3.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. Cohort 2: Dose Expansion Cohort 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. 4.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 of 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. Cohort 2: Dose Expansion Cohort 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. 5.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) (see Appendix 8 on Allowed Recent Second or Prior Malignancies for details). Prior or concurrent second malignancies must be reviewed and agreed to with the medical monitor. 6.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). 7.Must meet the following cohort-specific requirements: Cohorts 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 curative intent 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.Cohort 2: Pembrolizumab + Amivantamab d. Participant must be treatment-na?ve 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 systemic 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. 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. 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. 8.Have an ECOG performance status of 0 to 1 (Appendix 9). 9.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 (see Appendix 11). 10.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. 11.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 10^3/μL. c. Platelets >=100 x 10^3/μL. 12.Participants must meet the following cohort-specific requirements: Cohort 2: Pembrolizumab + Amivantamab Thyroid function laboratory values within the normal range. Note: If TSH is not within normal limits, the participant may still be eligible if triiodothyronine (either total or free) and free thyroxine are within normal limits. 13.While on study treatment and for 10 months after the last dose of study treatment, a participant must: Not breastfeed or be pregnant. Not donate gametes (ie, eggs or sperm) or freeze for future use for the purposes of assisted reproduction. Participants should consider preservation of gametes prior to study treatment as anticancer treatments may impair fertility. Wear an external condom. If of childbearing potential:o have a negative highly sensitive serum (β-hCG) pregnancy test at screening and within 72 hours of the first dose of study treatment, and agree to further pregnancy tests, o practicing at least 1 highly effective method of contraception; if oral contraceptives are used, a barrier method of contraception must also be used.If a participant’s partner is of childbearing potential: o the partner must practice a highly effective method of contraception unless the participant is vasectomized. See Appendix 4: Contraceptive and Barrier Guidance for details. 14.Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study. 15.Be willing and able to adhere to the lifestyle restrictions specified in this protocol.

1.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. Cohort 2: Pembrolizumab + Amivantamab 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; 2.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. 3.Known allergies, hypersensitivity, or intolerance to excipients of amivantamab or rHuPH20 (refer to the IB). Cohort 2: Pembrolizumab + Amivantamab 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). 4.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). Note: Participants with cardiac pacemakers who are clinically stable are eligible. 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) (NYHA Criteria are provided in the Appendix 10) within 6 months of the first dose of study treatment. Pericarditis/clinically significant pericardial effusion. Myocarditis. 5.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. 6.Participant with untreated brain metastases Note: Participants with definitively, locally treated metastases that are clinically stable and asymptomatic for at least 8 weeks and who are off or receiving low-dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 4 weeks prior to the first dose of study treatment are eligible. 7.Participant has a medical history or known presence of leptomeningeal disease, or participant has spinal cord compression not definitively treated with surgery or radiation. 8.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/mm^3 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; 9.Active hepatitis of infectious origin. a. Seropositive for hepatitis B: defined by a positive test for HBsAg. Participants with resolved infection (ie, participants who are HBsAg negative with anti-HBc with or without the presence of anti-HBs) must be screened using RT-PCR measurement of HBV DNA levels. Those who are RT-PCR positive will be excluded. Participants with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by RT-PCR (see Appendix 12, Hepatitis B Virus Screening). b. Positive hepatitis C antibody test result at screening or within 3 months prior to the first dose of study treatment. Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative HCV RNA test is obtained. c. Positive hepatitis C RNA test result at screening or within 3 months prior to the first dose of study treatment. Note: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. d. Other clinically active liver disease of infectious origin. 10.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. 11.Received radiotherapy for palliative purposes within 7 days of the first administration of study treatment. 12.Requires a prohibited medication that cannot be discontinued, substituted, or temporarily interrupted during the study; see Section 6.9, Concomitant Therapy for prohibited therapies; 13.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. 14.Cohort 2: Pembrolizumab + Amivantamab Prohibited immunosuppressive medication use (as detailed in Section 6.9.3) within 7 days prior to the first administration of study treatment. 15.Cohort 2: Pembrolizumab + Amivantamab 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. 16.Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.

None

None

NA

An electronic case report form for each subject is prepared and provided by the sponsor. All data related to the study must be recorded in the eCRF. All eCRF entry, correction, and modification must be performed by the investigator or authorized site staff. The investigator must verify the accuracy and correctness of all data entered into the eCRF. Study data will be transcribed into the eCRF from the source file by site staff (if applicable). Study-specific data will be transmitted to the sponsor in a secure manner. Worksheets can be used in some data acquisitions to assist with the eCRF. These worksheets will be considered part of the subject source file. Data must be entered into the eCRF in English. The eCRF must be completed as soon as possible after the subject completes the visit to ensure that the form can be reviewed at the next scheduled monitoring visit. Whenever possible, all participatory measures (e.g., pain scales or other questionnaires) should be completed by the person conducting the initial baseline assessment. If necessary, a challenge will be generated through the eDC tool. If the eCRF needs to be corrected after the initial eCRF entry, it can be done in any of the following ways: Investigators and site staff can take the initiative to use the eDC tool to make corrections or respond to automatically generated queries (generated by the eDC tool). Questions may be raised by the sponsor or the sponsor's representative, which will be addressed by the investigator or site staff.