Study of MT-8421 as Monotherapy and in Combination With Nivolumab in Patients With Selected Advanced Solid Cancer Types

NCT06034860 | Terminated Phase 1 FDA Drug

• 1 other identifier: MT-8421-001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 5

Brief Summary

This is a Phase 1, open-label, dose escalation and expansion study of MT-8421 (an Engineered Toxin Body (ETB)) as monotherapy and in combination with nivolumab in patients with selected advanced solid cancer types. MT-8421 is an investigational drug that specifically targets and depletes cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) expressing cells in an effort to directly dismantle the tumor microenvironment for the treatment of patients with advanced solid tumors.

Conditions

Non Small Cell Lung Cancer; Hepatocellular Carcinoma; Melanoma; Renal Cell Carcinoma; Microsatellite Instability High; Mismatch Repair Deficiency; Mesothelioma; Esophageal Squamous Cell Carcinoma; Squamous Cell Carcinoma of Head and Neck; Urothelial Carcinoma; Cervical Cancer

Outcome Measures

Primary Outcomes (3)

• Number of participants with Adverse Events

  Evaluation of safety and tolerability of MT-8421 as measured by number of participants with Adverse Events, dose limiting toxicities (DLTs), abnormal physical exam findings, abnormal laboratory test results, abnormal radiographic findings, and/or patient reported symptoms

  28 day cycle

• To confirm the recommended Phase 2 dose (RP2D) of MT-8421 as monotherapy and in combination with nivolumab in patients with selected advanced solid tumor types.

  Incidence of AEs

  28 day cycle

• Proportion of participants with objective response

  Objective response rate (ORR) defined as the proportion of participants with either a complete response or a partial response as determined by investigator assessment using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

  Up to two years (Part B)

Secondary Outcomes (11)

• Objective response rate to assess preliminary efficacy

  Up to two years (Parts A)

• Duration of response to assess preliminary efficacy

  Up to two years (Parts A)

• Time to response to assess preliminary efficacy

  Up to two years (Parts A)

• Progression-free survival to assess preliminary efficacy

  Up to two years (Parts A)

• Disease control rate to assess preliminary efficacy

  Up to two years (Parts A)

Study Arms (4)

Part A- Dose Escalation Monotherapy

EXPERIMENTAL

Part A- Dose escalation of MT-8421 monotherapy in patients with selected advanced solid tumors. The assigned dose level of MT-8421 will be given as an intravenous (IV) infusion over about 30 minutes on the same day every week (i.e. on day 1, day 8, day 15, and day 22 of each 28-day cycle).

Drug: MT-8421

Part A- Dose Escalation Combination Therapy

EXPERIMENTAL

Part A- Dose escalation of MT-8421 in combination with nivolumab in patients with selected advanced solid tumors. The assigned dose level of MT-8421 will be given as an intravenous (IV) infusion over about 30 minutes prior to the infusion of 480 mg nivolumab. MT-8421 will be given on the same day every week (i.e. on day 1, day 8, day 15, and day 22 of each 28-day cycle). Nivolumab will be given on the first day of each cycle beginning at cycle 2.

Drug: MT-8421; Drug: Nivolumab

Part B Dose Expansion Monotherapy

EXPERIMENTAL

Part B- Dose expansion of MT-8421 monotherapy in patients with selected advanced solid tumors. Part B monotherapy will include two expansion groups: Group B1 (NSCLC) and group B2 (HCC). The assigned dose level of MT-8421 determined in Part A will be given as an intravenous (IV) infusion over about 30 minutes on the same day every week (i.e. on day 1, day 8, day 15, and day 22 of each 28-day cycle).

Drug: MT-8421

Part B Dose Expansion Combination

EXPERIMENTAL

Part B- Dose escalation of MT-8421 in combination with nivolumab in patients with selected advanced solid tumors. Part B combination therapy will include two expansion groups: Group B3 (Melanoma) and Group B4 (RCC). The assigned dose level of MT-8421 determined in Part A will be given as an intravenous (IV) infusion over about 30 minutes prior to the infusion of 480 mg nivolumab. MT-8421 will be given on the same day every week (i.e. on day 1, day 8, day 15, and day 22 of each 28-day cycle). Nivolumab will be given on the first day of each cycle beginning at cycle 2.

Drug: MT-8421; Drug: Nivolumab

Interventions

MT-8421 DRUG

Experimental treatment with MT-8421

Part A- Dose Escalation Combination Therapy; Part A- Dose Escalation Monotherapy; Part B Dose Expansion Combination; Part B Dose Expansion Monotherapy

Nivolumab DRUG

480 mg nivolumab administered on Day 1 of each cycle starting with Cycle 2 for all combination dose escalation and dose expansion cohorts

Part A- Dose Escalation Combination Therapy; Part B Dose Expansion Combination

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed, unresectable, locally advanced, or metastatic melanoma, HCC, NSCLC, RCC, MSI-H/dMMR malignancies, urothelial carcinoma, esophageal squamous cell carcinoma, mesothelioma, SCCHN, or cervical carcinoma not amenable to standard treatment, or standard treatment is not available, or in the Investigator's opinion, the standard treatment would not be in the patient's best interest.
• Part A only: Evaluable only or measurable disease according to RECIST v1.1 Part B only: At least 1 measurable tumor lesion according to RECIST v1.1
• Prior treatment must include a PD-1 or programmed cell death - ligand 1 (PD-L1) inhibitor. Prior treatment with a CTLA-4 inhibitor is not required.
• Eastern Cooperate Oncology Group (ECOG) performance score of 0 or 1
• Adequate bone marrow function, as determined by:
• Absolute neutrophil count (ANC) ≥ 1500/ μL (should not have received growth factors within 2 weeks prior to screening)
• Platelet count ≥ 75,000/ μL
• Hemoglobin ≥ 8.0 g/dL (no red blood cell transfusion within 2 weeks of study treatment start is allowed)
• Adequate renal function, based on estimated creatinine clearance (eCrCl) ≥ 50 mL/min, calculated by the Cockcroft-Gault equation.
• Adequate hepatic function, as determined by:
• Total bilirubin ≤ 1.5x upper limit of normal (ULN) or ≤ 2x ULN direct bilirubin for patients with Gilbert's Syndrome
• Aspartate transaminase (AST) ≤ 3x ULN (or ≤ 5x ULN if liver metastasis or HCC).
• Alanine transaminase (ALT) ≤ 3x ULN (or ≤ 5x ULN if liver metastasis or HCC).
• Adequate serum albumin (albumin ≥ 2.5 g/dL)
• Availability of a lesion that can be biopsied with acceptable risk.

You may not qualify if:

• Unwilling or unable to undergo 2 sets of 3 to 6 core tumor biopsies: one set at study baseline (prior to first dose of study drug) and one set between Weeks 6 through 8. A final optional set will be collected time of disease progression.
• Received tremelimumab within 30 days or ipilimumab 3 mg/kg within 60 days or ipilimumab 1 mg/kg within 30 days before the start of treatment. Once dose cohort of 32 µg/kg MT-8421 has been completed in dose escalation, a 30-day washout of ipilimumab is acceptable irrespective of prior dose.
• Any concurrent cancer treatment, apart from local treatment of non-target lesions for palliative intent (e.g., local surgery or radiotherapy). Patient must have recovered from the effects of the local treatment and be discussed with the medical monitor.
• History or current evidence of another neoplastic disease, except cervical carcinoma in situ; superficial non-invasive bladder tumors, curatively treated; Stage I to II non-melanoma skin cancer; prostate cancer managed by active surveillance; or any previous cancer curatively treated \< 2 years before the start of treatment.
• Active autoimmune disease that required systemic treatment in the past. Patients who have not required systemic treatment for at least 2 years may be enrolled if permission is provided after discussion with the Medical Monitor (replacement therapy, e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency is allowed)
• Evidence of active, non-infectious ≥ Grade 2 pneumonitis or current evidence of ≥ Grade 3 other underlying pulmonary disease.
• Ongoing \> Grade 1 immune-related toxicity caused by prior CPI therapy (i.e., PD-1 inhibitors, PDL1 inhibitors, or CTLA-4 inhibitors). Patients with stable endocrinological AEs (e.g., hypothyroidism, adrenal insufficiency, hypopituitarism, or diabetes mellitus) must have been on a stable dose of supplemental therapy for at least 2 weeks before screening to be eligible for this study. History of repeat Grade 2 pneumonitis or myocarditis on previous CPI and/or Grade 3 irAE on previous CPI treatment.
• Current evidence of new or growing central nervous system (CNS) metastases during screening. Patients with known CNS metastases will be eligible if they meet all the following criteria:
• Received radiotherapy or another appropriate therapy for the CNS metastases, if clinically Indicated
• Have stable CNS disease on the computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the ICF compared with prior neuroimaging.
• History or current evidence of significant cardiovascular disease before the start of treatment.
• Current evidence of active, uncontrolled hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV) (evidenced by detectable viral load by polymerase chain reaction) or acquired immunodeficiency syndrome (AIDS)-related illness.
• Serology and virology measurements are not required to be performed at screening, but any previously reported results should be used for eligibility purposes. Investigators will test per their discretion
• Patients with a history of treated hepatitis C and non-quantifiable hepatitis C virus- ribonucleic acid (RNA) may be enrolled.
• Patients on treatment for hepatitis B, hepatitis C, and/or HIV will be eligible if they have undetectable viral load (patients with HIV with CD4+ T-cell \[CD4+\] counts ≥ 350 cells/µL may be enrolled).

Sponsors & Collaborators

• Molecular Templates, Inc.: lead

Study Sites (5)

The Angeles Clinic

Los Angeles, California, 90025, United States

Location

Horizon Oncology Research, LLC

Lafayette, Indiana, 47905, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Weill Cornell Medicine

New York, New York, 10065, United States

Location

NEXT Oncology

Fairfax, Virginia, 22031, United States

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Carcinoma, Hepatocellular; Melanoma; Carcinoma, Renal Cell; Turcot syndrome; Mesothelioma; Esophageal Squamous Cell Carcinoma; Squamous Cell Carcinoma of Head and Neck; Carcinoma, Transitional Cell; Uterine Cervical Neoplasms

Interventions

Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Liver Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Adenoma; Neoplasms, Mesothelial; Carcinoma, Squamous Cell; Neoplasms, Squamous Cell; Esophageal Neoplasms; Gastrointestinal Neoplasms; Head and Neck Neoplasms; Esophageal Diseases; Gastrointestinal Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Genital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Admasu Mamuye, MD

  Molecular Templates

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2023
• First Posted: September 13, 2023
• Study Start: November 1, 2023
• Primary Completion: October 31, 2024
• Study Completion: October 31, 2024
• Last Updated: November 1, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (5)