Study to Evaluate IMGS-001 Treatment in Patients With Relapsed or Refractory Advanced Solid Tumors

A Phase 1a/1b, Open-label, Dose-escalation, and Dose-expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Anti-tumor Activity of IMGS-001 in Patients With Relapsed or Refractory Advanced Solid Tumors

The purpose of this Phase 1a/1b clinical trial is to test the safety of an investigational drug called IMGS-001 and to determine how well it can work in treating patients with advanced solid tumors that have come back or are not improving after receiving other drugs that are commonly used for their cancer. Phase 1a (Part 1) will test the safety of five different doses of IMGS-001 to use in further studies. Patients with cancer that have advanced or spread to other parts of the body following treatment with other available therapies will be treated in Part 1. Phase 1b (Part 2) will test two doses of IMGS-001 identified in Part 1 to further determine the safety and potential effectiveness in select cancer types.

Part 1 is a Phase 1a, first-in-human, open-label dose-escalation study to determine the safety, tolerability, and maximum tolerated dose (MTD) of IMGS-001. The safety, tolerability, PK parameters, and preliminary antitumor activity of IMGS-001 will be assessed in adult patients with advanced solid tumors refractory to appropriate standard of care (SOC) treatments.

Based on the MTD and other information (e.g., tolerability, PK, PD, target engagement), multiple doses of IMGS-001 will be selected for further evaluation. Additional subjects may be backfilled across Phase 1a doses (or other intermediate doses at or below the MAD/MTD) to assure adequate clinical data to support dose optimization and selection of appropriate doses for use in the Phase 1b. Approximately 35 total subjects will be enrolled in Phase 1a.

Part 2 is a Phase 1b, open-label, dose-expansion study of five prespecified tumor cohorts to assess preliminary antitumor activity of IMGS-001 in patients that are refractory or intolerant to other appropriate prior standard therapies. Stage 1 will consist of two separate cohort designs: 4 single-dose cohorts and 1 tumor specific dose optimization cohort in NSCLC.

The 4 single dose Stage 1 cohorts will initially enroll approximately 10 subjects in each of the following cohorts treated with IMGS-001:

• Cohort 1: Ovarian cancer (high-grade epithelial, fallopian tube, or primary peritoneal; PD-L1 positive [CPS ≥1])
• Cohort 2: 9p24.1 lymphomas (classic Hodgkin's, PMBCL)
• Cohort 3: Nasopharyngeal cancer (non-keratinizing)
• Cohort 4: Head and neck squamous cell carcinoma (HPV+, PD-L1 positive [CPS ≥1])

Each cohort will be assessed to meet efficacy criteria to continue into a randomized dose-optimization. Within each cohort that meets prespecified efficacy criteria, the expanded cohorts will have randomly assigned (1:1) subjects to receive one of two doses used in the Phase 1a. Within each Arm, 20 eligible subjects will be treated with the assigned dose of IMGS-001.

For the Stage 1 dose optimization in the NSCLC cohort, approximately 20 subjects will initially be randomized 1:1 to one of two dose arms. If efficacy criteria are met, the cohort may be expanded to randomize approximately 20 additional subjects across these two doses.

Inclusion Criteria:

• Part 1 Dose-escalation: Patients must have histologically confirmed locally advanced, or metastatic solid tumors who have progressed after receiving appropriate lines of standard therapy known to potentially confer clinical benefit.

• Part 2 Dose-expansion: Patients must have histologically confirmed locally advanced, or metastatic cancer in one of the following pre-specified tumor types and meet tumor-specific criteria:

  1. Nasopharyngeal: non-keratinizing; ≤ 2 prior lines of therapy in relapse setting; patients should have received prior chemotherapy and/or immune checkpoint blockade as per SOC.
  2. 9p24.1 Lymphomas (classic Hodgkin's, PMBCL): post first line therapy and completion of salvage regimens (including ASCT) with curative intent per SOC.
  3. Ovarian (high-grade epithelial, fallopian tube, or primary peritoneal): platinum resistant disease defined as progression within < 6 months from completion of a platinum-based chemotherapy regimen; platinum refractory subjects are excluded (defined as disease that has recurred/progressed while receiving platinum-based frontline therapy). ≤ 3 prior lines of therapy in relapse setting; may be naive or exposed to prior checkpoint therapy; may have received prior folate receptor alpha (FRα) antibody-drug conjugate (ADC), other targeted therapies, and/or PARPi as appropriate per SOC; confirmed PD-L1 CPS ≥1.
  4. NSCLC (non-mutated, squamous/non-squamous): ≤ 2 prior lines of therapy in relapse setting; patients could have received prior chemotherapy, immune checkpoint blockade, or targeted therapy in earlier lines of therapy as per SOC; confirmed PD-L1 CPS ≥1 or TPS ≥50%.
  5. Head and neck squamous cell carcinoma (HPV+): ≤ 2 prior lines of therapy in relapse setting; patients could have received prior chemotherapy, immune checkpoint blockade, or cetuximab as appropriate per SOC; confirmed PD-L1 CPS≥1.

• Patients eligible to enroll in cohorts with prior immune checkpoint therapy must meet the following criteria:

  1. Received at least 2 doses of an approved or investigational anti PD-1 or anti-PD-L1 inhibitor.
  2. Last dose of therapy must have been ≥ 28 days prior to Cycle 1 Day 1.
  3. Eligible patients include those patients treated with anti PD-1/anti PD-L1 drugs who have progressed following response to prior therapy, and those that have failed to demonstrate any response to prior therapy.

• Ovarian cancer, HNSCC, and NSCLC patients participating in Part 2 (Phase 1b) must have confirmed PD-L1 positive expression (CPS ≥ 1 or TPS ≥ 50% [NSCLC only]).

• Male or female ≥ 18 years of age.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• Life expectancy > 3 months.

• At least 1 measurable lesion as defined by RECIST 1.1. Subjects with lymphoma must have measurable disease as per Lugano Criteria (2014).

• Patients must have a non-target lesion that can be biopsied. If a patient only has one target lesion (and no non-target lesions) the target lesion used for biopsy must be ≥ 2 cm in longest diameter.

• Patients must have adequate bone marrow and organ function as defined by:

  1. Absolute neutrophil count (ANC) ≥ 1.5×10^9/L.
  2. Platelet count of ≥ 100.0×10^9/L.
  3. Hemoglobin of ≥ 9.0 g/dL.
  4. Creatinine clearance ≥ 30 mL/min.
  5. Liver function test: AST (SGOT) and ALT (SGPT) ≤ 2.5 times the institutional ULN.
  6. Total bilirubin: ≤ 1.5 x ULN.

Exclusion Criteria:

• Receipt of any investigational or conventional anti-cancer drug/therapy within 21 days of Cycle 1 Day 1.
• Current or prior use of immunosuppressive medication within 14 days of Cycle 1 Day 1 except those required in the protocol pre-medication regimen. Inhaled and intranasal corticosteroids are allowed.
• Current or prior use of interleukin-2, interferon, or other immunotherapy medication within 28 days of Cycle 1 Day 1.
• Live vaccine within 28 days prior to Cycle 1 Day 1.
• Any toxicity from prior standard therapy that has not resolved to ≤ Grade 1 or baseline per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 at the time of consent. Alopecia is an exception. Any patients with irreversible Grade 1 or Grade 2 toxicities that are considered stable may be enrolled after discussion with the Medical Monitor.
• Prior anti-PD-1 or anti-PD-L1-related Grade 3 or Grade 4 toxicity resulting in treatment discontinuation of the drug.
• Secondary malignancy other than the target malignancy to be investigated in this trial within the last 2 years. Subjects with a history of carcinoma in situ, basal cell carcinoma and other malignancies with low risk of recurrence, that have been curatively treated and have not progressed, and are under surveillance may be enrolled.
• History of myocardial infarction, ischemic heart disease, symptomatic congestive heart failure (New York Heart Association (NYHA) Class III IV), or significant cardiac arrhythmias within 3 months of study enrollment.
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) or pulmonary embolism within 3 months of study enrollment.
• History of acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal carcinomatosis, bowel perforation, or other known risk factors for bowel perforation.
• Active, uncontrolled, or prior documented autoimmune disorders including but not limited to inflammatory bowel disease (including Crohn's disease and ulcerative colitis), rheumatoid arthritis, systemic sclerosis (scleroderma), Systemic Lupus Erythematosus, or autoimmune vasculitis (e.g., Wegener's Granulomatosis). Alopecia, vitiligo, celiac disease controlled by diet, and chronic skin conditions not requiring systemic therapy/immunosuppressive treatment is permitted.
• Uncontrolled intercurrent illness, including active infection requiring systemic therapy, uncontrolled hypertension (> 150/90mm Hg despite optimal medical management), uncontrolled asthma, psychiatric illness/social situations, substance abuse, or other underlying medical conditions that would limit compliance with study requirements, obscure the interpretation of AEs, substantially increase the risk of developing AEs, or make the administration of study treatment hazardous.
• Active human immunodeficiency virus (HIV) infection (Exception: patients with well-controlled HIV [e.g., CD4 ≥ 350 cells/uL and undetectable viral load] who have been on an effective [drug, dosage, and schedule associated with reduction and control of the viral load] antiretroviral therapy [ART] for ≥ 4 weeks are eligible). Patients with a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last 12 months are not eligible.
• Active or chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with a history of HCV infection must have completed curative antiviral treatment and must have a viral load below the limit of quantification. A patient who is HCV antibody (Ab) positive but HCV RNA negative due to prior treatment or natural resolution is eligible.
• History of solid organ transplantation.
• Newly diagnosed, uncontrolled, and/or untreated cancer-related central nervous system disease. Patients with treated brain metastases that are radiographically or clinically stable for at least 28 days after therapy and have no evidence of cavitation or hemorrhage in the brain lesion(s) are eligible if they are asymptomatic and do not require corticosteroids (the patient must have discontinued steroids at least 14 days prior to Cycle 1 Day 1).
• Major surgery, open biopsy, or significant traumatic injury within 28 days of Cycle 1 Day 1, or still recovering from prior surgery. Port placement and other local procedures are allowed if completed at least 48 hours prior to Cycle 1 Day 1.
• Abnormal pulmonary function within the previous 6 months prior to Cycle 1 Day 1, including history of or active pneumonitis, interstitial lung disease requiring the use of steroids, idiopathic pulmonary fibrosis, recurrent pleural effusion (including malignant origin), severe dyspnea at rest or requiring supplementary oxygen therapy. Subjects with pleural effusions that are small and not clinically significant (e.g. not causing shortness of breath) are eligible with Medical Monitor approval.
• Patients who have experienced any infusion related reaction Grade 3 or higher from prior therapy per NCI CTCAE version 5.0