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Carcinoma, Adenosquamous

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Irinotecan

Leucovorin

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Pancrelipase

Pancreatin

The lead-in dose de-escalation cohort (Phase 1b) will enroll 6 patients (up to 12 patients in 2 dose levels if needed; 6 patients per DL) to receive zimberelimab, domvanalimab, and APX005M

Participants will be randomly assigned to one of two groups

Arm A will receive domvanalimab, zimberelimab, and APX005M every two weeks through an infusion.

Arm B will receive leucovorin, fluorouracil, and irinotecan every two weeks through an infusion

Participants in Arm B (control arm) who experience disease progression (as defined by RECIST v1.1) will be given the option to crossover and receive domvanalimab + zimberelimab, + APX005M in the second-line setting, provided they meet eligibility criteria

Via IV on two days per cycle, dosage per protocol

ZIMBERELIMAB

DOMVANALIMAB

APX005M

every two weeks through an infusion at a dose determined by physician

FOLFIRI

James Cleary, MD, PhD

This study is being done to test the safety and effectiveness of combining domvanalimab (AB154), zimberelimab (AB122), and APX005M with pancreatic cancer that has spread to other parts of body.

This research study involves immunotherapy. Immunotherapy triggers the body's immune system to fight cancer cells.

The names of the study drugs involved in this study are:

* Domvanalimab (also known as AB154)
* Zimberelimab (also known as AB122)
* APX005M

This is an open-label, Phase 1b/2, multicenter, randomized study evaluating the safety and efficacy of 'switch maintenance' combination immunotherapy (domvanalimab) zimberelimab and APX005M versus 'continuous maintenance' in patients with metastatic pancreatic cancer following 4-6 months of FOLFIRINOX

The names of the study drugs involved in this study are:

* Domvanalimab (also known as AB154)
* Zimberelimab (also known as AB122)
* APX005M

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

Participants will be randomized into one of two groups:

* Arm A will receive domvanalimab, zimberelimab, and APX005M every two weeks through an infusion.
* Arm B will receive leucovorin, fluorouracil, and irinotecan every two weeks through an infusion

If you are in Arm B and the drugs stop working, participants may receive the drugs given in Arm A.

Participants will receive study treatment as long the disease does not worsen or there are no serious side effects for a maximum of 26 cycles (2 years) and will be followed for 12 months after the discontinue the study drugs.

It is expected that about 46 people will take part in this research study.

This is a Phase I/II clinical trial. A Phase I clinical trial tests the safety of an investigational drug or drugs and also tries to define the appropriate dose of the investigational drug(s) to use for further studies. Phase II clinical trials test the safety and effectiveness of an investigational drug or drugs to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The U.S. Food and Drug Administration (FDA) has not approved domvanalimab, zimberelimab, or APX005M as a treatment for any disease.

drug regimen.

Switch Maintenance in Pancreatic

Phase Ib/II Open-Label, Multicenter, Randomized Study Evaluating the Safety and Efficacy of 'Switch Maintenance' Combination Immunotherapy Using AB154, AB122, and APX005M in Patients With Metastatic Pancreatic Cancer

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Toxicity assessments will be evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

PFS is defined as the time from registration to the Crossover Arm to the earlier of progression or death due to any cause.

The PFS2 distribution will be calculated and plotted using the Kaplan-Meier method

Tumor reassessment with baseline CT scan and restaging scans will occur every 8 weeks using RECIST v1.1

The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).

Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation

Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive

Arcus Biosciences, Inc.

Lustgarten Foundation

Sponsor Investigator

Participants will be provided with a bottle of pemigatinib tablets on Day 1 of each cycle (one cycle = 21 days). A bottle contains 4.5 mg X 42 tablets total. Each pemigatinib bottle is sufficient for one cycle. Resupply will be provided as necessary on Day 1 of each cycle.

Pemigatinib 4.5 mg tablets taken 3 times per day \[daily dose of 13.5 mg (3 tablets)\] for 14 consecutive days followed by 7 days off medication in 21-day cycles

Doses will be self-administered at home. Participants will be instructed to take study medication at the same time each day, with or without food.

Pemigatinib 4.5 MG

Erkut Borazanci, MD

The purpose of this research is to determine the benefit of pemigatinib in patients with advanced metastatic or surgically unresectable adenosquamous carcinoma of the pancreas who have progressed on previous therapy.

Pemigatinib in Subjects With Adenosquamous Carcinoma of the Pancreas

Efficacy and Safety of Pemigatinib in Subjects With Advanced Metastatic or Surgically Unresectable Adenosquamous Carcinoma of the Pancreas (ASCP) Who Have Progressed On Previous Therapy

Overall response rate of pemigatinib in patients with advanced metastatic or surgically unresectable ASCP who have progressed on previous therapy

To determine progression free survival (PFS)

To determine the overall safety (medical risk to the subject) and tolerability (the degree to which adverse effects can be tolerated by the subject) of pemigatinib in patients with advanced metastatic or surgically unresectable ASCP who have progressed on previous therapy

Incyte Corporation

HonorHealth Research Institute

Reproductive Control Agents

Triptolide

14-O-phosphonooxymethyltriptolide disodium salt

Antineoplastic Agents, Alkylating

Alkylating Agents

Minnelide 2mg Days 1-21 of 28 day cycle (x12)

Administered orally (2 mg) once daily for 21 days of 28-day cycles for 12 cycles.

Minnelide

NCI Medical Oncology Referral Office

Christine C Alewine, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Pancreatic cancer is one of the most lethal types of cancer. ASCP is a highly aggressive type of pancreatic cancer. It is very rare. Researchers want to see if a drug called Minnelide can be used to treat ASCP.

Objective:

To see if Minnelide is an effective treatment for ASCP.

Eligibility:

Adults ages 18 and older with ASCP whose cancer did not respond to previous treatments.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine samples

Evaluation of ability to do daily activities

Electrocardiogram to test heart function

Body and/or brain scans. For these, participants will lie in a machine that takes pictures of the body. They may have a contrast agent injected into a vein.

Tumor sample. If one is not available, participants will have a tumor biopsy. The biopsy will be taken with a small needle put through the skin into the tumor.

Treatment will be given in 28-day cycles, for up to 12 cycles. There is a 7-day resting period between cycles. Participants will take Minnelide by mouth every day for 21 days of each cycle. They will keep a medicine diary.

Participants will have at least 1 study visit every cycle. They will review their medicine diary. They will repeat some screening tests.

Participants may have optional tumor biopsies. Some participants may need to take birth control during the study and for up to 6 months after treatment.

Participants will have an end-of-treatment visit 4 weeks after they stop taking the study drug. They will repeat some screening tests.

Background:

* Adenosquamous carcinoma of the pancreas (ASCP) is a highly aggressive variant of pancreatic ductal adenocarcinoma (PDA), the most common type of pancreas cancer.
* ASCP is estimated to account for 0.5-4% of the 55,000 people who are diagnosed with pancreatic cancer in the U.S. each year, making it a very rare tumor type.
* No prospective clinical trials specific to ASCP have ever been performed.
* Preclinical data in ASCP models indicate that an activated superenhancer network drives epigenetic changes which cause the prognostically unfavorable squamous differentiation.
* Genomic analysis of ASCP tumors identifies frequent amplification of MYC.
* Minnelide is a small molecule anti-superenhancer drug that inhibits MYC.
* The recommended dose of Minnelide has previously been established through clinical testing for other indications.

Primary Objective:

-To determine the single agent antitumor activity (disease control rate) of the anti-superenhancer agent Minnelide in participants with advanced, previously treated ASCP

Eligibility:

* Age \>= 18 years
* Histologically confirmed ASCP or high suspicion for ASCP based on histologic analysis
* for squamous markers
* Participants with metastatic or locally advanced unresectable disease and progression on at least 1 prior treatment regimen

Design:

* This is a phase II single cohort clinical trial with one arm.
* The number of evaluable participants needed for the primary endpoint is 25; maximum accrual set at 55 participants (accounting for screen failures and inevaluable participants).
* iNITIALparticipants will receive Minnelide at 2 mg/day PO on Days 1-21 of a 28 day cycle.
* Later participants will receive a higher dose of 2.5 mg/day PO on the same schedule.
* Treatment will be continued for up to 12 cycles (1 year) in the absence of disease progression or unacceptable toxicity.
* Treatment response will be assessed by imaging every 2 cycles (8 weeks).
* Optional tumor biopsies will be requested mid-cycle 1 and at time of progression.
* A disease control rate of \>= 40% in this highly refractory population would constitute a positive study. Up to 12 participants will treated be initially. If 3 of the 12 participants have a response, then up to 13 additional participants will be entered to determine the true response rate.

Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)

A Phase II Trial of the Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)

.All IPD recorded in the medical record will be shared with intramural investigators upon request.@@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

To determine the single agent antitumor activity (disease control rate = CR+PR+stable x16 weeks) of the anti-superenhancer agent Minnelide in participants with advanced, previously treated ASCP

The length of time from the start of treatment that patients diagnosed with the disease are still alive.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Switch Maintenance in Pancreatic	NCT05419479	Pancreatic Canc... Adenocarcinoma ... Squamous Cell C... Adenosquamous C...	ZIMBERELIMAB DOMVANALIMAB APX005M FOLFIRI	18 Years -	Dana-Farber Cancer Institute
Pemigatinib in Subjects With Adenosquamous Carcinoma of the Pancreas	NCT05216120	Pancreas Cancer	Pemigatinib 4.5...	18 Years - 100 Years	HonorHealth Research Institute
Superenhancer Inhibitor Minnelide in Advanced Refractory Adenosquamous Carcinoma of the Pancreas (ASCP)	NCT04896073	Adenosquamous C...	Minnelide	18 Years -	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for adenosquamous carcinoma of the pancreas