M7824 (MSB0011359C) in Combination With Gemcitabine in Adults With Previously Treated Advanced Adenocarcinoma of the Pancreas

Phase 1

Terminated

• Conditions: Pancreatic Adenocarcinoma; Pancreatic Neoplasms; Pancreas Cancer; Cancer of Pancreas; Pancreatic Cancer
• Interventions: Drug: M7824; Drug: Gemcitabine

• Registration Number: NCT03451773
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

Background:

Pancreas cancer ranks 4th in all cancer-related deaths in the United States (U.S.) Gemcitabine is a standard treatment for it. M7824 (MSB0011359C) blocks a pathway that prevents the immune system from effectively fighting cancer. The two drugs together might help people with pancreas cancer.

Objective:

To test if giving M7824 together with gemcitabine is safe and causes tumors to shrink.

Eligibility:

People ages 18 and older with pancreatic cancer already treated with standard therapies

Design:

Participants will be screened with:

Medical history

Physical exam

Scans in a machine that takes pictures of the body

Blood, urine, and heart tests

Some participants may have a tumor sample removed.

Participants will get M7824 by intravenous (IV) once every 2 weeks. They will continue until their disease gets worse or they have unacceptable side effects.

After the first dose, participants will also get gemcitabine by IV once weekly for 7 weeks. Then they will get it as follows for up to 6 months: Skip 1 week, get the drug once a week for 3 weeks, skip 1 week.

Before treatment on the first day of each cycle, participants will repeat screening tests. They will also have:

Optional tumor biopsies before and after 3 cycles of therapy

Questions about their well-being and function

Genetic testing of tissue and blood samples

Participants will have a follow-up visit 4-5 weeks after they stop therapy. This includes a physical exam, blood and urine tests, and maybe a scan. If their disease does not get worse, they will be invited for scans every 12 weeks.

Detailed Description

Background:

* M7824 (MSB0011359C) is an investigational agent in phase IB/II clinical development with dual activity against transforming growth factor beta (TGF)-beta signaling (TGF-beta ligand trap; extracellular domain of human TGF-beta receptor II) and immune checkpoint ligand inhibition (PD-L1 inhibition; avelumab, fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) directed against human PD-L1) with an acceptable toxicity profile and early signals of anti-cancer activity including in pancreas cancer.

* Gemcitabine (2 \<=,2 \<=-Difluorodeoxycytidine) is a standard-of-care nucleoside analogue in pancreas cancer with immunomodulatory mechanisms of actions in pancreas cancer patients.

* Preclinical studies in autochthonous and syngeneic murine models have shown that TGF-beta inhibition and PD-L1 inhibition cooperate with gemcitabine to achieve reduction of tumor growth and extension of survival induce anti-tumor immunity and reprogram the immune landscape.

Objectives:

* To determine the safety and tolerability of M7824 in combination with gemcitabine in subjects with metastatic or locally advanced pancreas cancer.

* To determine best overall response (BOR) rate according to Response Evaluation Criteria (Response Evaluation Criteria in Solid Tumors (RECIST) 1.1) in advanced pancreas cancer subjects.

Eligibility:

* Histologically confirmed diagnosis of adenocarcinoma of the pancreas.

* Patients must have progressed on prior chemotherapeutic regimen.

* Concurrent treatment with non-permitted drugs and other interventions, prior therapy with gemcitabine or any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such as anti-PD 1, anti PD-L1, or anti-cytotoxic T lymphocyte antigen-4 (CTLA 4 antibody) is not allowed.

Design:

- The proposed study is a phase IB/II study of M7824 in combination with gemcitabine in a safety run-in of 6-18 patients and, if safe and tolerated, will proceed to an expansion phase II cohort with a standard Simon Minimax design.

Study Timeline

• Study First Submitted: 2018-03-01
• Study First Submitted QC: 2018-03-01
• Study First Posted: 2018-03-02
• Study Start: 2018-05-17
• Primary Completion: 2020-05-05
• Study Completion: 2020-05-05
• Results First Submitted: 2021-03-07
• Status Verified: 2021-05
• Results First Submitted QC: 2021-05-27
• Last Update Submitted: 2021-05-27
• Results First Posted: 2021-06-16
• Last Update Posted: 2021-06-16

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 7

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
2/ Arm 2-Gemcitabine + Recommended Phase 2 Dose (RP2D) of M7824 (MSB0011359C)	M7824	Gemcitabine (dose based on genetic testing results) + RP2D of M7824
1/ Arm 1-Gemcitabine + de-escalating dose of M7824 (MSB0011359C)	M7824	Gemcitabine (dose based on genetic testing results) + de-escalating dose of M7824
1/ Arm 1-Gemcitabine + de-escalating dose of M7824 (MSB0011359C)	Gemcitabine	Gemcitabine (dose based on genetic testing results) + de-escalating dose of M7824
2/ Arm 2-Gemcitabine + Recommended Phase 2 Dose (RP2D) of M7824 (MSB0011359C)	Gemcitabine	Gemcitabine (dose based on genetic testing results) + RP2D of M7824

Primary Outcome Measures

Name	Time	Method
Phase IB: Number and Severity of Grade 1-2 Adverse Events Possibly, Probably, or Definitely Related to Treatment	30 days after treatment	Safety and tolerability of M7824 in combination with gemcitabine was assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 1 is mild; asymptomatic or mild symptoms. Grade 2 is moderate; minimal non-invasive intervention indicated.
Duration of Treatment-related Adverse Events (AEs)	Time to resolution of adverse events, which is the time recorded until it took for the adverse event to resolve to grade 1 or less (if there is a death, it is that time), approximately 12 months.	Duration of treatment-related AE's is defined as the time from the date treatment consent signed to end of treatment. Grade 1-4 adverse events observed in participants with pancreatic cancer assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v5.0. Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe or medically significant. And Grade 4 is life-threatening.
Phase II: Number of Participants With a Best Overall Response (BOR)	Every 8 weeks, up to 2 years	Changes in tumor size and occurrence of metastases was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 to determine the best overall response: Complete Response (CR), Partial Response (PR), and Stable Disease (SD), whichever is recorded first. Complete Response is disappearance of all lesions, Partial Response is at least a 30% decrease in the sum of diameters of target lesions, and Stable Disease is when the sum of all target lesions does not qualify for CR, PR, or Progressive Disease (PD), defined as the appearance of new lesions.
Phase IB: Number and Severity of Grade 3-5 Adverse Events Possibly, Probably, or Definitely Related to Treatment	30 days after treatment	Safety and tolerability of M7824 in combination with gemcitabine was assessed by the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 3 is severe or medically significant but not immediately life-threatening, Grade 4 is life-threatening consequences, and Grade 5 is death related to adverse event.

Secondary Outcome Measures

Name	Time	Method
Percentage of Evaluable Participants Alive at 6 Months and 9 Months	At 6 and 9 months	Participants who are alive at 6 months and 9 months after therapy.
Number of Participants With an Immune-related Best Overall Response (irBOR)	Every 6-12 weeks, up to 1 year	irBOR is defined as the duration of immune-related best overall response measured from the time measurement criteria are met for Immune-related Complete Response (irCR) or Immune-related Partial Response (irPR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Immune related changes in tumor size and occurrence of metastases was assessed by the Modified Immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). Immune-related Complete Response (irCR) is complete disappearance of all lesions and no new lesions. Immune-related Partial Response (irPR) is sum of the longest diameters of target and new measurable lesions neither irCR, irPR (compared to baseline) or irPD (compared to nadir). Immune-related Progressive Disease (irPD) is appearance of new lesions.
Percentage of Participants Who Have Not Progressed at 3 Months	3 months	Percentage of participants who have not progressed at 3 months. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of new lesions.
Overall Median Survival	up to 1 year	OS is the median amount of time subject survives after therapy.
Overall Progression Free Survival	up to 6 months	PFS is the median amount of time subject survives without disease progression after treatment. Progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as the appearance of new lesions.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center; 🇺🇸 Bethesda, Maryland, United States