A Phase II Study of Adjuvant Immunotherapy Targeting KRAS G12D, KRAS G12V, or TP53 R175H for Participants With Advanced Gastrointestinal Malignancies

Background:

-Despite definitive surgical resection and (neo)adjuvant chemotherapy, many patients with gastrointestinal carcinomas (GIC) remain at high risk of recurrence and disease-specific mortality. This includes virtually all patients with resected pancreas ductal adenocarcinoma

(PDAC), patients with resected colorectal liver, lung, and/or lymph node metastases (CRLM) with persistently elevated circulating tumor DNA (ctDNA) after resection, and patients with localized GIC (other than PDAC) with persistently elevated ctDNA after resection (GIC). These patients need systemic therapies that can prevent recurrence by eradicating occult micrometastatic disease.

-We have safely treated patients with metastatic GIC using adoptive cell transfer (ACT) autologous tumor-infiltrating lymphocytes (TIL) and with peripheral blood lymphocytes transduced with a T-cell receptor (TCR) specific for a shared hot-spot mutation in KRAS

or TP53 (TCR T-cell therapy). We have demonstrated that TIL can mediate long-term responses in patients with metastatic GIC, providing proof of concept that cell transfer can be effective in low tumor mutational burden, microsatellite stable epithelial cancers, and

can eradicate occult micrometastatic disease. Now, we have also demonstrated that TCR T-cell therapy directed against KRAS G12D, KRAS G12V, and TP53 R175H can mediate objective responses in metastatic GIC.

-Despite some success, practical and theoretical barriers have hampered the translation of TCR T-cell therapy for metastatic GIC. There is evidence that late-stage disease and especially a higher disease burden is associated with resistance to immunotherapy.

Moreover, accumulated toxicity from exposure to cytotoxic chemotherapy may damage the lymphocytes on which TCR T-cell therapy depends. Finally, patients with extensive history of progressive cancer and chemotherapy exposure have depleted physiologic

reserves which can hamper their tolerance of and recovery from cellular therapy. Given these considerations, cellular therapy could be more effective and better tolerated in patients who have a lower burden of disease and are earlier in their disease course.

Objective:

-To determine recurrence-free survival (RFS) (using Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 criteria) of participants treated with TCR T-cells (Arm 1) versus no experimental therapy (Arm 2).

Eligibility:

• Age >= 18 years and <= 72 years.
• PDAC, CRLM, or GIC as follows:
• PDAC
• Resected PDAC of stage I-III, and history of detectable ctDNA after resection/local treatment of all known disease.

OR

---If stage I-III, has a history of abnormally elevated cancer antigen (CA)19-9 at diagnosis (before surgery) AND a history of abnormally elevated post-operative CA19-9 after surgery AND a relative increase of post-operative CA19-9 of 2.6-fold compared to the participant s post-operative baseline, as confirmed by two separate tests at least 3 weeks apart.

OR

• Had metastatic disease (stage IV) at diagnosis and were down staged with chemotherapy and underwent resection. --CRLM
• Stage IV colorectal cancer with metastases that were completely treated with local therapy and have a history of detectable ctDNA after resection/local treatment of all known disease. --GIC
• Participants with resected gastroesophageal cancer, hepatocellular cancer, cholangiocarcinoma, duodenal, small bowel or primary colorectal cancer (i.e., pathologic stage I-III as distinguished from CRLM) and history of detectable ctDNA after resection/local treatment of all known disease.
• No evidence of measurable disease.
• History of:
• KRAS G12D mutation plus HLA-A*11:01
• KRAS G12D mutation plus HLA-C*08:02
• KRAS G12V mutation plus HLA-C*01:02
• TP53 R175H mutation plus HLA-A*02:01
• Adequate basic laboratory values

Design:

• Eligible participants will be randomized in a 1:1 fashion after successful completion of apheresis under 03-C-0277 and verification of a sufficient PBL sample for use for TCR Tcell therapy.
• Participants randomized to Arm 1 will return to NIH to receive TCR T-cells plus aldesleukin following lymphodepletion with reduced-dose cyclophosphamide and fludarabine. Participants randomized to Arm 2 will return to the NIH for surveillance.
• There will be three strata for randomization:

1. Pancreas cancer
2. Stage IV colorectal cancer
3. Other gastrointestinal cancers (including stage I-III colorectal cancer)

• TCR T-cells are generated by transduction of autologous peripheral blood lymphocytes (PBL) with TCR genes encoding a T-cell receptor that recognizes a hotspot mutation in KRAS G12D, KRAS G12V, or TP53 R175H in the context of HLA.
• Participants randomized to Arm 2 will receive no experimental therapy but will have serial clinical evaluation and surveillance on the same schedule as participants in Arm 1.
• Baseline clinical evaluation and radiographic assessment will be performed on all participants before randomization, and both arms will undergo radiographic evaluation on the same schedule every 3-6 months thereafter.
• It is anticipated that approximately two participants per month will be randomized. There will be a limit of 30 evaluable participants per Arm for a total of 60 evaluable participants. Thus, the accrual may be completed in approximately 2.5 years.