A Study of the Safety and Tolerance of CAN04 and Pembrolizumab in Combination With and Without Carboplatin and Pemetrexed in Subjects With Solid Tumors

Study Overview
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Brief Summary
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This study will consider the safety and effectiveness of a study drug, CAN04, in combination with pembrolizumab, in the treatment of incurable or metastatic non-small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma, urothelial cancer, or malignant melanoma. The study aims to establish a recommended dose of CAN04 in combination with the standard dose of pembrolizumab (Part 1), and in combination with pembrolizumab standard dose, and Standard of Care carboplatin and pemetrexed (Part 2 - subjects with stage IV, non-squamous metastatic NSCLC). CAN04, pembrolizumab. carboplatin and pemetrexed will be administered intravenously.

Official Title
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An Open-label, Safety and Tolerability Phase 1b Trial of CAN04, a Fully Humanized Anti-IL1RAP Monoclonal Antibody, and Pembrolizumab in Combination With and Without Carboplatin and Pemetrexed in Subjects With Solid Tumors

Conditions
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Carcinoma, Non-Small-Cell Lung, Urothelial Carcinoma, Malignant Melanoma, Head and Neck Squamous Cell Carcinoma

Intervention / Treatment
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* Drug: CAN04
* Drug: Pembrolizumab
* Drug: Carboplatin
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Part 1): Subjects with metastatic or locally advanced, incurable non-small-cell lung cancer (NSCLC [adenocarcinoma, adenosquamous, or squamous]), head and neck squamous cell carcinoma (HNSCC), urothelial cancer, or malignant melanoma who have exhausted or declined available standard therapy. Subjects progressing on previous treatment with a checkpoint inhibitor targeting thePD-1/PD-L1 pathway, alone or in combination with chemotherapy after previously having achieved stable disease or better and stayed on such therapy for ≥12 weeks. Primary or metastatic lesion suitable for biopsy and willingness to undergo repeat biopsies as appropriate. Willing and able to provide intravenous access for the administration of the study drug and for blood sampling/testing. Inclusion Criteria (Part 2): Subjects with histologically confirmed non-squamous metastatic (stage IV) NSCLC, without option for locoregional treatment with curative intent. Subjects who have not received prior systemic anti-cancer therapy for the locally advanced or metastatic NSCLC. Subjects who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease. Ability to safety undergo pre-treatment (if no archival biopsy is available) and on-treatment tumor biopsies. Subject consents to retrieval of archival tumor tissue for screening in case no fresh biopsy is performed during screening. Willing and able to provide intravenous access for the administration of the study drug and for blood sampling/testing. Exclusion Criteria (Parts 1 and 2): Subjects with NSCLC tumors with genetic alteration or mutation, for which FDA-approved targeted therapy is available. Treatment with systemic anticancer treatments, investigational products, or major surgery within 4 weeks before first dose of study drug or 5 half-lives, whichever is shorter. Subjects should have recovered from previous treatment toxicity (except hair loss and peripheral neuropathy). History of uncontrolled brain metastasis. Subject has received extended field radiotherapy ≤4 weeks before the start of treatment (≤2 weeks for limited field radiation to alleviate symptoms), and who has not recovered from related side effects of such therapy (except for hair loss). Subjects who have previously experienced an immune-related adverse event (irAE) to pembrolizumab, for which permanent discontinuation is required. Subjects without a formal contraindication due to previous irAE are not eligible if the AE has not resolved or requires steroids (>10 mg prednisone-equivalent per day) for ongoing management. Subjects with active severe infection requiring oral antibiotics. Clinical evidence of an active second invasive malignancy with the exception of stable prostate cancer on watchful waiting. Uncontrolled or significant cardiovascular disease. History of autoimmune disease requiring systemic immunosuppressive therapy (daily prednisone equivalent doses >10 mg/day). HIV patients can be enrolled if the infection is adequately controlled. Known bleeding disorder or coagulopathy. Subjects on stable anticoagulant therapy are allowed. Known or suspected allergy to study treatment or related products. Women who are pregnant or breastfeeding, or trying to become pregnant. Patients with chronic viral hepatitis. Exclusion criteria (Part 2): Previous therapy with immunotherapy (anti-PD-1, anti-PD-L1, and anti-PD-L2, anti-CTLA-4, or other approved or investigational checkpoint-inhibitors). Subject is unable or unwilling to take folic acid or vitamin B12 supplementation. Subject is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDS), other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day period for long-acting agents, such as piroxicam). Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAN04 and pembrolizumab (Part 1)<br>Subjects will receive weekly doses of CAN04 in combination with pembrolizumab given as standard regimen | Drug: CAN04<br>* Administered intravenously<br>Drug: Pembrolizumab<br>* Administered intravenously<br>|
| Experimental: CAN04 + pembrolizumab + carboplatin + pemetrexed (Part 2)<br>Subjects will receive doses of CAN04 on Days 1 and 8 (Cycles 1 thru 4), and on Day 1 (Cycle 5 onwards) in combination with pembrolizumab given as standard regimen and carboplatin and pemetrexed standard of care | Drug: CAN04<br>* Administered intravenously<br>Drug: Pembrolizumab<br>* Administered intravenously<br>Drug: Carboplatin<br>* Administered intravenously<br>Drug: Pemetrexed<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of TEAEs (treatment-emergent adverse events) (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Frequency of TEAEs (treatment-emergent adverse events) (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of participants with DLTs (dose-limiting toxicities) (Part 1) |  | Up to day 28 | 
| Number of participants with DLTs (dose-limiting toxicities) (Part 2) |  | Up to day 28 | 
| Number of subjects with grade ≥3 TEAEs (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with grade ≥3 TEAEs (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with grade ≥3 TEAEs (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with grade ≥3 TEAEs (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with 1 or more SAEs (serious adverse events) (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with 1 or more SAEs (serious adverse events) (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with 1 or more SAEs (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with 1 or more SAEs (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with 1 or more TEAEs leading to dose modifications (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with 1 or more TEAEs leading to dose modifications (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with 1 or more TEAEs leading to treatment discontinuation (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Number of subjects with 1 or more TEAEs leading to treatment discontinuation (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with 1 or more TEAEs leading to dose modifications (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with 1 or more TEAEs leading to dose modifications (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with 1 or more TEAEs leading to treatment discontinuation (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Percentage of subjects with 1 or more TEAEs leading to treatment discontinuation (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentrations of CAN04 and pembrolizumab (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Serum concentrations of CAN04 and pembrolizumab (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Antidrug antibodies (ADAs) against CAN04 |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Change in serum IL-6 (interleukin-6) concentration (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Change in serum IL-6 (interleukin-6) concentration (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Change in serum CRP (C-reactive protein) concentration (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Change in serum CRP (C-reactive protein) concentration (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Overall response rate (ORR) (Part 1) | Proportion of subjects with partial response (PR) or complete response (CR) to study treatment as defined by iRECIST (immune-related response evaluation criteria in solid tumors) and measured by radiological assessment (CT/MRI scan) | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Overall response rate (ORR) (Part 2) | Proportion of subjects with partial response (PR) or complete response (CR) to study treatment as defined by iRECIST (immune-related response evaluation criteria in solid tumors) and measured by radiological assessment (CT/MRI scan) | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Progression free survival (Part 1) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Progression free survival (Part 2) |  | From the first dose until the last subject has completed their end of trial visit or the last enrolled subject has completed 6 months of treatment, whichever comes first | 
| Overall survival (Part 1) |  | Up to 36 months after 1st dose of last subject (or death) | 
| Overall survival (Part 2) |  | Up to 36 months after 1st dose of last subject (or death) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC, Adenocarcinoma of lung, Lung cancer, Squamous cell lung cancer, Malignant melanoma, Urothelial cancer, Non-small-cell lung cancer, Non small cell lung cancer, Non-small-cell lung carcinoma, Non small cell lung carcinoma, HNSCC, Head and neck squamous cell carcinoma