FORTRAS: A Study of MSK-TCR5 in People With Solid Tumor Cancers

FORTRAS: Phase I, Investigator Initiated, Dose-escalation Clinical Trial Evaluating a CD8 Alpha/Beta Armored RAS G12D/HLA-A*11:01-specific T-cell Receptor Therapy (MSK-TCR5) in Patients With Advanced Solid Tumors

The purpose of this study is to test the safety of MSK-TCR5 in participants with advance solid tumor cancer that has a KRAS, HRAS, or NRAS G12D mutation.

Inclusion Criteria:

Part A: Prior to cell collection all of the following inclusion criteria must be met:

• Age ≥18 years.

• Histologically confirmed advanced or metastatic, unresectable solid tumor

• Positive for RAS G12D mutation and HLA-A*11:01 allele

• Subject has advanced solid cancer, defined as unresectable, advanced, and/or metastatic disease after at least 1 line of systemic standard of care (SOC) treatment regimen and for which there are no available curative treatment options. Subjects with stable disease (SD), or that present lack of clinical benefit from previous therapy (including treatment suspension due to toxicity) may be considered eligible for enrollment. :

  1. For CRC: Patients harboring genomic aberrations such as BRAFV600E mutations, HER2 amplifications, or VEGF expression for which FDA-approved targeted therapies are available must have received prior treatment with applicable FDA-approved targeted therapies, including multi-kinase inhibitors. Patients whose tumors have deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) must have received an immune checkpoint inhibitor prior to enrolling in this study.
  2. For NSCLC: Patients harboring genomic aberrations such as non-resistant EGFR mutations, ALK rearrangement, ROS rearrangement, and BRAF V600E mutation for which FDA-approved targeted therapies are available must have received prior treatment with the applicable FDA-approved targeted therapies. Patients with the appropriate PD-L1 expression score must have received treatment with an FDA-approved checkpoint inhibitor with or without chemotherapy consistent with the FDA-approved label.
  3. Any other solid tumors, including PDAC: Patients harboring genomic aberrations for which FDA-approved targeted therapies are available must have received prior treatment with the applicable FDA-approved targeted therapies. Patients whose tumors have dMMR/MSI-H must have received an immune checkpoint inhibitor prior to enrolling in this study.

Part B: Prior to treatment with MSK-TCR5 all of the following inclusion criteria must be met:

• Measurable disease per RECIST version 1.1. Note: a previously irradiated or locoregionally treated lesion can be considered a target lesion if it progressed post-treatment.

• ECOG performance status of 0 or 1

• Adequate organ and bone marrow function based on the following laboratory values:

  1. ANC ≥1000/mm3 without granulocyte colony-stimulating factor support (filgrastim within 7 days or peg-filgrastim within 14 days of screening)
  2. Platelets ≥75,000/mm3 without transfusion within the preceding 7 days of screening.
  3. Hemoglobin ≥8.0 g/dL (≥80 g/L); blood transfusion permitted within 7 days of screening.
  4. AST, ALT, and ALP ≤ 3x ULN, or ≤ 5x ULN if liver or bone metastases present.
  5. Total bilirubin ≤ 1.5x ULN or ≤ 3x ULN in the presence of documented Gilbert's Syndrome
  6. CrCl ≥50 mL/min by Cockcroft-Gualt equation

Exclusion Criteria:

Part A: Participant Exclusion Criteria prior to cell collection

• Previous allogeneic stem cell transplantation or prior organ transplantation

• History of primary immunodeficiency, autoimmune, or inflammatory disease including inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, or Grave's disease that in the past year has required systemic treatment with corticosteroids > 10mg/day of prednisone or equivalent doses of other corticosteroids or immunosuppressive drugs. Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal/pituitary insufficiency is not considered a form of systemic treatment and allowed)

• Primary brain tumor

• Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or cord compression. Patients previously treated for CNS metastases that are radiographically and neurologically stable and off steroids for at least 2 weeks prior to enrollment are eligible.

• Surgery or catheter-based interventions such as transarterial chemoembolization or percutaneous coronary intervention within 2 weeks.

• Uncontrolled significant intercurrent or recent illness including, but not limited to the following conditions:

  a. Significant cardiovascular abnormalities as defined by any one of the following: uncontrolled congestive heart failure or hypertension, clinically significant hypotension, symptomatic coronary artery disease, or a documented ejection fraction (EF) of < 50% as assessed by echocardiogram or multigated acquisition scan (MUGA).

• Uncontrolled active bacterial, viral, fungal, or mycobacterial infection not responding to antibiotics, antimycotics, or antifungal agents, as well as long-term oral treatment with any of these agents.

• Subject has had radiotherapy or systemic anti-cancer therapy within at least 2 weeks or 3 half-lives, whichever is shorter.

• Pregnant or lactating women; women of childbearing age, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception while receiving study treatment and for at least 12 months after all treatment is finished. Sexually active males, unless they are willing to use a condom during intercourse while receiving study treatment and for at least 12 months after all treatment is finished.

• Previously identified allergy, hypersensitivity, or known contraindication to cyclophosphamide, fludarabine, or any other agent associated with LDC or MSK-TCR5.

• Positive serologic test results for HIV.

• Acute or chronic HBV infection as assessed by serologic (HBVsAg) or PCR results, defined as HBVsAg+, HBVcAb+, HBV PCR+.

• Acute or chronic HCV infection as assessed by serologic (HCV ab) or PCR results, defined as HCV Ab+ with reflex to positive HCV PCR

• Patient/parent/LAR unable to give informed consent

Part B: Participant Exclusion Criteria prior to MSK-TCR5 infusion

• Any exclusion criterion listed in Part A.