A Phase 1/2a Study of IMM-1-104 in Participants With Previously Treated, RAS-Mutant, Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, dose-exploration and expansion study to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of IMM-1-104 when administered as monotherapy or in combination with approved agents in participants with RAS-mutated or RAS/MAPK activated advanced or metastatic solid tumors. The dose exploration will identify the candidate recommended Phase 2 dose (RP2D) of IMM-1-104 to further explore the anti-tumor activity of IMM-1-104 as monotherapy and in combination with approved agents in multiple Phase 2a proof-of-concept cohorts in malignancies of interest.

Official Title
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A Phase 1/2a, Open-Label, Multicenter, Nonrandomized, Safety and Anti-tumor Activity Study of IMM-1-104, a Novel Oral Dual MEK1/2 Inhibitor in Participants With Previously Treated RAS-Mutated Advanced or Metastatic Solid Tumors

Conditions
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Advanced Solid Tumor, Pancreatic Adenocarcinoma, Malignant Melanoma (Cutaneous), Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: IMM-1-104 Monotherapy (Treatment Group A)
* Drug: IMM-1-104 + modified Gemcitabine/nab-Paclitaxel (Treatment Group B)
* Drug: IMM-1-104 + modified FOLFIRINOX (Treatment Group C)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be ≥18 years of age Must have histologically or cytologically confirmed diagnosis as follows: Monotherapy Phase 1: A locally advanced unresectable or metastatic solid tumor malignancy that harbors a RAS (KRAS, NRAS, or HRAS) activating mutation. Monotherapy Phase 2a: A locally advanced unresectable or metastatic solid tumor malignancies: pancreatic ductal adenocarcinoma (PDAC), RAS-mutant melanoma, or RAS-mutant non-small cell lung cancer (NSCLC) Combination therapy (both phases): A locally advanced unresectable or metastatic PDAC Participants must be treatment naive or received prior systemic standard-of-care treatment as follows: Monotherapy Phase 1: received at least 1 line of systemic standard-of-care treatment for their advanced or metastatic disease Monotherapy Phase 2a: First-line PDAC participants will have received no previous systemic anti-cancer therapy. Second-line PDAC participants will have received no more than one prior systemic anti-cancer therapy. First-line melanoma participants will have received no previous systemic anti-cancer therapy. Second- and third-line participants will have received and failed one or two prior systemic anti-cancer therapies, respectively. NSCLC participants will have received at least one and no more than two previous lines of systemic therapy. Combination therapy (both phases): PDAC participants will have received no previous systemic anti-cancer therapy for their advanced or metastatic disease. Must have evidence of measurable disease (at least one target lesion) per RECIST v1.1 criteria Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate organ function Exclusion Criteria: Inability to swallow oral medications Symptomatic, untreated, or actively progressing known central nervous system (CNS) metastases History or concurrent evidence of retinal vein occlusion (RVO) or current risk factors for RVO. History of serous retinopathy, retinal edema, or retinal pigment epithelial detachment (RPED) Impaired cardiovascular function or clinically significant cardiac disease History of rhabdomyolysis within 3 months prior to start of study treatment Active skin disorder requiring systemic treatment within 3 months prior to the start of study treatment Females who are pregnant, breastfeeding, or planning to become pregnant and males who plan to father a child while enrolled in this study.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group A<br>IMM-1-104 Monotherapy | Drug: IMM-1-104 Monotherapy (Treatment Group A)<br>* Once-daily, oral IMM-1-104 dose administered in 28-day cycles until treatment discontinuation criteria are met<br>* Other names: IMM-1-104;|
| Experimental: Treatment Group B<br>IMM-1-104 in combination with modified gemcitabine and nab-paclitaxel (mGnP) | Drug: IMM-1-104 + modified Gemcitabine/nab-Paclitaxel (Treatment Group B)<br>* Once-daily, oral IMM-1-104 dose administered in 28-day cycles in combination with intravenous infusions of gemcitabine and nab-paclitaxel until treatment discontinuation criteria are met. Gemcitabine will be administered at a dose of 1000 mg/m^2 nab-Paclitaxel will be administered at a dose of 125 mg/m^2<br>* Other names: IMM-1-104 + mGnP;|
| Experimental: Treatment Group C<br>IMM-1-104 in combination with modified FOLFIRINOX (mFFX) | Drug: IMM-1-104 + modified FOLFIRINOX (Treatment Group C)<br>* Once-daily, oral IMM-1-104 dose administered in 28-day cycles in combination with intravenous infusions of modified FOLFIRNOX until treatment discontinuation criteria are met. FOLFIRINOX will be administered as follows: Folinic Acid will be administered at 400 mg/m^2 Fluorouracil will be administered at 2400 mg/m^2 Irinotecan will be administered at 150 mg/m^2 Oxaliplatin will be administered at 85 mg/m^2<br>* Other names: IMM-1-104 + mFFX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Adverse Events | Number of participants with adverse events | From treatment initiation through 30 days following the last IMM-1-104 dose | 
| Phase 1: Dose-Limiting Toxicities | Number of participants with dose-limiting toxicities | The first 21 days of study treatment | 
| Phase 1: Recommended Phase 2 Dose (RP2D) candidate | Selection of candidate RP2D to take forward into Ph2a | Initiation of study treatment through 21 days (up to approximately 18 months) | 
| Phase 2a: Overall Response Rate | The proportion of participants who achieve a best overall response (BOR) of complete response (CR) or partial response (PR), based on RECIST 1.1 criteria | After up to 48 weeks (12 cycles) of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1/2a: Maximum Observed Plasma Concentration of IMM-1-104 | Cmax | After 12 weeks (3 Cycles) of study treatment | 
| Phase 1/2a: Time to Reach Maximum Plasma Concentration of IMM-1-104 | Tmax | After 12 weeks (3 Cycles) of study treatment | 
| Phase 1/2a: Area Under Plasma Concentration (AUC) Time Curve of IMM-1-104 | AUC0-t | After 12 weeks (3 Cycles) of study treatment | 
| Phase 2a: Disease Control Rate (DCR) | The proportion of participants who have a best overall response (BOR) of stable disease (SD) or better | After 16 weeks (4 Cycles) of study treatment | 
| Phase 2a: Progression Free Survival (PFS) | The time interval between study treatment start and disease progression or death due to any cause. | Up to approximately 2 years | 
| Phase 2a: Duration of Response (DOR) | The time interval between an assessment of partial response (PR) or better and disease progression or death due to any cause. | Up to approximately 2 years. | 
| Phase 2a: Landmark 3-Month Survival | The proportion of participants who are still alive after three months on study. | After 3 months of study participation. | 
| Phase 2a: Landmark 6-Month Survival | The proportion of participants who are still alive after six months on study. | After 6 months of study participation. | 
| Phase 2a: Overall Survival (OS) | The time interval between study treatment start and death due to any cause. | Up to approximately 2 Years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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G12C, Q61H, Q61K, G12D, G12F, G12R, G12S, G12V, G13C, G13D, G13R, pan-RAS, KRAS, NRAS, HRAS, Targeted therapy, Metastatic cancer, Advanced cancer, RAS, Adenocarcinoma, MEK, Dual MEK, MEK 1/2, Mitogen-Activated Protein Kinase (MAPK), G12A, Q61L, Q61R, A146T, A146V, K117N