IMM60 and Pembrolizumab in Melanoma and NSCLC

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn about IMM60 with or without pembrolizumab in participants with advanced melanoma or non-small cell lung cancer. There are two phases: Phase 1: This phase is designed to learn about the safety of IMM60 with or without pembrolizumab and to find a safe dose to test in Phase 2. Phase 2: This phase is designed to learn whether IMM60 + pembrolizumab improves progression-free survival at 12 months compared to pembrolizumab alone in participants with non-small cell lung cancer.

Detailed Description
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This exploratory phase 1/phase 2 study is designed to establish a recommended phase 2 dose of IMM60 and provide preliminary estimates of safety and efficacy of IMM60 alone and in combination with pembrolizumab in participants with NSCLC and melanoma. In phase 1, initial safety will be assessed in a multiple dose escalation cohort for IMM60 alone, then for the IMM60 + pembrolizumab combination. Phase 2 of the study will recruit PD-1 pretreated melanoma participants and randomize PD-L1 > 50% total NSCLC participants 2:1 to IMM60 + pembrolizumab vs pembrolizumab alone. There is an additional cohort of PD-L1 < 1% NSCLC participants.

Official Title
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IMPORT-201: A Phase 1 First-in-Human Dose Finding/Randomized Phase 2 Study of IMM60 and Pembrolizumab for Advanced Melanoma and Metastatic NSCLC

Conditions
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Non-small Cell Lung Cancer, Melanoma

Intervention / Treatment
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* Drug: IMM60
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score 0 to 1 Adequate organ function At least 1 lesion, not previously irradiated, that can be accurately measured on CT or MRI as defined by RECIST 1.1 criteria NSCLC cohorts: Histologically confirmed diagnosis of stage IV NSCLC NSCLC cohorts: Patients with adenocarcinoma histology must not have sensitizing epidermal growth factor receptor (EGFR) or ROS proto-oncogene 1 (ROS1) mutations or anaplastic lymphoma kinase (ALK) translocations NSCLC cohorts: Participants in NSCLC arms must have a PD-L1 assessment (PD-L1 immuno-histochemistry (IHC) 22C3 pharmDx) Melanoma cohorts: Unresectable stage III or IV, histologically confirmed diagnosis of cutaneous or unknown primary melanoma Melanoma cohorts: B-type Raf proto-oncogene (BRAF) mutation status available Male participants: Participant must agree to use contraception and refrain from sperm donation during the treatment period and for at least 120 days after the last dose of study intervention Female participants: Participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 6 months after the last dose of study intervention Exclusion Criteria: Has the following cardiac conditions: Corrected QT interval (QTc) > 450 ms Uncontrolled hypertension with blood pressure (BP) > 160/100 despite treatment Class II or greater heart failure as defined by the New York Heart Association Myocardial infarction within 6 months or angina requiring nitrate therapy more than once a week Another active malignancy within the past 2 years (Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder, or carcinoma in situ [e.g., breast carcinoma, cervical cancer in situ] that have undergone potentially curative therapy are not excluded. Also, prostate, breast, and neuroendocrine tumors that are stable on hormonal treatment for a period of 1 year or more without the need to adjust dose are not excluded.) Has had an allogeneic tissue/solid organ transplant Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable. History of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease Participants with an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids (in dosing exceeding 10 mg daily of prednisone equivalent) or immunosuppressive agents. Participants who are known to be serologically positive for Hepatitis B, Hepatitis C, or human immunodeficiency virus.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 IMM60 dose escalation safety arm<br>3 dose levels of IMM60 will be assessed (1, 3, 9 and 36 mg/m^2 administered IV every 3 weeks for up to 6 cycles) | Drug: IMM60<br>* IMM60, every 3 weeks for up to 6 cycles, intravenous (IV) infusion<br>* Other names: PORT-2;|
| Experimental: Phase 1 IMM60 + pembrolizumab combination safety arm<br>Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles will be administered in combination with IMM60 IV every 3 weeks for up to 6 cycles. The IMM60 dose will be determined based on the results of the IMM60 dose escalation safety cohort. | Drug: IMM60<br>* IMM60, every 3 weeks for up to 6 cycles, intravenous (IV) infusion<br>* Other names: PORT-2;Drug: Pembrolizumab<br>* Pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles or approximately 2 years, intravenous (IV) infusion<br>* Other names: Keytruda;|
| Experimental: Phase 2 PD-L1 ≥50% NSCLC Cohort 1 (Randomized, IMM60 + pembrolizumab)<br>Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles will be administered in combination with IMM60 IV every 3 weeks for up to 6 cycles. The IMM60 dose will be determined based on the results of the Phase 1 dose escalation safety cohorts. | Drug: IMM60<br>* IMM60, every 3 weeks for up to 6 cycles, intravenous (IV) infusion<br>* Other names: PORT-2;Drug: Pembrolizumab<br>* Pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles or approximately 2 years, intravenous (IV) infusion<br>* Other names: Keytruda;|
| Active Comparator: Phase 2 PD-L1 ≥50% NSCLC Cohort 1 (Randomized, pembrolizumab monotherapy)<br>Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles. | Drug: Pembrolizumab<br>* Pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles or approximately 2 years, intravenous (IV) infusion<br>* Other names: Keytruda;|
| Experimental: Phase 2 PD-L1 <1% NSCLC Cohort 2<br>Participants will be treated with one cycle of IMM60 with a tumor biopsy before and after, to determine any changes in PD-L1 expression. After this one cycle, the participants will receive the combination of IMM60 IV for up to 6 total cycles + pembrolizumab 200 mg every 3 weeks administered IV. The IMM60 dose will be determined based on the results of the Phase 1 dose escalation cohorts. | Drug: IMM60<br>* IMM60, every 3 weeks for up to 6 cycles, intravenous (IV) infusion<br>* Other names: PORT-2;Drug: Pembrolizumab<br>* Pembrolizumab, 200 mg, every 3 weeks for up to 35 cycles or approximately 2 years, intravenous (IV) infusion<br>* Other names: Keytruda;|
| Experimental: Melanoma Cohort<br>IMM60 IV every 3 weeks for up to 6 cycles. The IMM60 dose will be determined based on the results of the Phase 1 dose escalation cohorts. | Drug: IMM60<br>* IMM60, every 3 weeks for up to 6 cycles, intravenous (IV) infusion<br>* Other names: PORT-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Co-Primary Objective - Identify Maximum Tolerated Dose (MTD) | To confirm the maximum tolerated dose (MTD) of IMM60 alone and in combination with pembrolizumab, defined as the highest dose level at which <2 out of 6 participants experience a dose-limiting toxicity | Assessed at the end of Cycle 1 for each patient (each Cycle is 28 days) | 
| Phase 1 Co-Primary Objective - Safety | To characterize the safety of IMM60 alone and in combination with pembrolizumab, as assessed by the frequency of Grade 3 or higher treatment-related adverse events | Through Phase 1 completion, an average of 1 year | 
| Phase 2 Primary Objective - Progression-free Survival | To compare the progression-free survival (PFS) rate at 12 months in the randomized arms comparing pembrolizumab alone versus IMM60 + pembrolizumab in patients with advanced PD-L1 ≥50% NSCLC | 12 months after last participant enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterize the safety of IMM60 alone or in combination with pembrolizumab | Frequency and severity of treatment-related adverse events (AEs) | Through study completion, an average of 3 years | 
| To determine if IMM60 can restore sensitivity in PD-1 inhibitor-resistant melanoma (phase 2) | Objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 in melanoma patients who have progressed on PD-1, and have added IMM60 | 12 months after last participant enrolled | 
| Pharmacokinetics of IMM60 - Cmax (IMM60 arms only) | IMM60 maximal concentration (Cmax) | During Cycles 1 and 3 (each Cycle is 28 days) | 
| Pharmacokinetics of IMM60 - AUC (IMM60 arms only) | IMM60 area under the curve (AUC) | During Cycles 1 and 3 (each Cycle is 28 days) | 
| Objective Response Rate (ORR) | ORR is to be reported as the proportion of patients who have a Complete Response or Partial Response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 | 12 months after last participant enrolled | 
| To determine if IMM60 can sensitize patients with programmed death-ligand 1 (PD-L1) <1% NSCLC to PD-1 inhibition | Objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 in PDL1 <1% NSCLC patients who receive IMM60 + pembrolizumab | 12 months after last participant enrolled | 
| To assess the ability of IMM60 to convert PD-L1 negative patients to PD-L1 positive | Percent of PD-L1 negative (<1%) NSCLC tumors that increase PD-L1 gene expression following treatment with IMM60 | 12 months after last participant enrolled | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Invariant natural killer T cells (iNKT), Programmed Cell Death-1 (PD1, PD-1)