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Immune Checkpoint Inhibitor M7824 and the Immunocytokine M9241 in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Advanced Pancreas Cancer

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ClinicalTrials.gov Identifier: NCT04327986
Recruitment Status : Recruiting
First Posted : March 31, 2020
Last Update Posted : May 14, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Fewer than 10 percent of people with pancreas cancer can have surgery. Surgery gives the best outcome. Radiation therapy is usually used to make surgery possible. But it does not work for most people. Adding immunotherapy might help.

Objective:

To find a safe combined dose of M7824, M9241, and radiation and to see if it causes pancreas cancer tumors to shrink.

Eligibility:

People ages 18 and older who have pancreas cancer and cannot have curative surgery

Design:

Participants will be screened under protocol 01-C-0129 with:

Medical history

Physical exam

Heart, urine, and blood tests

Scans. For this, participants will lie in a machine that takes pictures of the body. They may receive a contrast agent by vein.

Possible tumor biopsy

Participants will take the study drugs either alone or with radiation. They will get M7824 by vein every 2 weeks. They will get M9241 injected under the skin every 4 weeks. Participants who get radiation will get it 5 days in a row the first month.

Participants will have visits every 2 weeks. They will repeat screening tests.

If participants tumors shrink, they will have surgery. If their whole tumor is removed, they will stop treatment. They will otherwise continue treatment as long as they can tolerate it and it is helping them.

Participants will have visits 1 week and 1 month after they stop treatment. Then they will be contacted by phone or email for life. If they stop treatment for a reason other than their disease getting worse, they will have scans every 12 weeks.


Condition or disease Intervention/treatment Phase
Histologically or Cytologically Confirmed Pancreatic Cancer Unresectable or Borderline Resectable Pancreatic Cancer Pancreatic Neoplasms Pancreatic Cancer Metastatic Pancreatic Cancer Drug: M7824 Drug: M9241 Radiation: SBRT Phase 1 Phase 2

Detailed Description:

Background:

  • At time of diagnosis, fewer than 10% of newly diagnosed pancreatic cancer patients present with resectable disease (patients who can undergo surgery) and patients able to undergo a margin-negative surgical resection (R0) are reported to have the most favorable outcome.
  • Locally advanced, non-metastatic pancreas cancer (LAPC) is observed in up to 30% of all pancreas cancer patients at time of diagnosis (including both borderline resectable and non-resectable disease).
  • The primary goal of neoadjuvant therapy in LAPC is, among tumor control and extension of survival, the conversion to resectable disease achieving a R0 resection.
  • Radiation therapy (RT) is commonly used as neoadjuvant treatment for LAPC.
  • However, currently used RT neoadjuvant treatment regimens result in only about 40%-60% of patients with borderline resectable pancreas cancer to undergo surgical resection, in initially unresectable LAPC patient conversion are even lower, with only 7% - 19% able to undergo resection.
  • Combining immunotherapy and radiation therapy could synergistically improve anti-cancer activity.
  • M7824 is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody functioning as an immune checkpoint inhibitor and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap.
  • The M9241 immunocytokine is composed of 2 IL-12 heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded DNA. M9241 targets delivery of IL12, a proinflammatory cytokine that has been shown anti-tumor activity including objective responses in phase I clinical trials, to regions of tumor necrosis where DNA has become exposed, e.g. after radiation therapy.
  • We hypothesize that released neo-epitopes upon increased DNA damage induced by radiation therapy together with the local proinflammatory action of M9241 will complement the anti-tumor activity of M7824 in locally advanced pancreas cancer.

Objectives:

  • To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 and M9241 in combination with SBRT as neoadjuvant/perioperative treatment in subjects with pancreas cancer.
  • To determine a preliminary estimate of efficacy as best overall response (BOR) according to RECIST 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant/perioperative treatment in subjects with locally advanced pancreas cancer.

Eligibility:

  • Histologically or cytologically proven pancreatic adenocarcinoma.
  • Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) (Cohorts 2-3).
  • Patients must have measurable disease.
  • Age greater than or equal to 18 years

Design:

  • This is an open label Phase I/II trial. During phase I the safety and tolerability of M7824 and M9241 will be evaluated and recommended Phase II dose (RP2D) of M7824 and M9241 in combination with SBRT will be estimated. During phase II efficacy of the M7824 and M9241 in combination with SBRT will be examined.
  • Patients will receive treatment in cycles consisting of 28 days (with exception of additional administer of M7824 alone in Phase IA).
  • Treatment will continue until unacceptable toxicity or disease progression.
  • If during treatment patient become candidate for curative surgery, treatment will be stopped and can be restarted after surgery in case if surgical exploration does not result in the successful removal of the tumor.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 52 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of the Immune Checkpoint Inhibitor M7824 and the Immunocytokine M9241 in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Advanced Pancreas Cancer
Estimated Study Start Date : May 19, 2021
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 1/Arm 1A
De-escalating doses of M9241 in combination with M7824
Drug: M7824
IV on Days 1 and 15 of every cycle

Drug: M9241
Subcutaneous injection on Day 1 of every cycle

Experimental: 2/Arm 1B
De-escalating doses of M9241 in combination with M7824 and SBRT
Drug: M7824
IV on Days 1 and 15 of every cycle

Drug: M9241
Subcutaneous injection on Day 1 of every cycle

Radiation: SBRT
Radiation therapy will be starting on Day 17 (+5 days) of Cycle 1 and continue for 5 consecutive business days.

Experimental: 3/Arm 2
RP2D of M7824 and M9241 in combination with SBRT
Drug: M7824
IV on Days 1 and 15 of every cycle

Drug: M9241
Subcutaneous injection on Day 1 of every cycle

Radiation: SBRT
Radiation therapy will be starting on Day 17 (+5 days) of Cycle 1 and continue for 5 consecutive business days.




Primary Outcome Measures :
  1. To determine a preliminary estimate of efficacy as best overall response (BOR) according to RECIST 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant/perioperative treatment in subjects with locally advanced pancreas cancer [ Time Frame: every 2 months ]
    Dividing the number of patients with an objective response by the number of evaluable patients who are treated at the MTD and reported along with two sided 80% and 95% confidence intervals

  2. To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in subjects with pancreas cancer [ Time Frame: 28 days after completion of treatment ]
    Number, severity, and duration of treatment-related AEs for the combination treatment of M7824 and M9241 administered in combination with a 5-day course of SBRT and rate of completion of neoadjuvant SBRT courses when given with M7824 and M9241


Secondary Outcome Measures :
  1. To assess overall survival (OS) in patients after completion of RT in combination with M9241 and M7824 [ Time Frame: death ]
    Kaplan-Meier curves

  2. To asses progression-free survival (PFS) for all participants [ Time Frame: at progression ]
    Kaplan-Meier curves

  3. To asses progression-free survival (PFS) for participants who did not undergo surgical resection [ Time Frame: at progression ]
    Kaplan-Meier curves

  4. To determine fraction of patients with LAPC who are able to undergo surgical resection after M7824 and M9241 in combination with SBRT treatment [ Time Frame: at time of surgical resection ]
    Fraction of patients with LAPC who are able to undergo surgical resection after M7824 and M9241 in combination with SBRT treatment.

  5. For patients who underwent surgical resection after M7824 and M9241 in combination with SBRT treatment to determine time-to-recurrence of the disease [ Time Frame: disease recurrence after surgical resection ]
    Kaplan-Meier curves

  6. For patients who underwent surgical resection after M7824 and M9241 in combination with SBRT treatment to determine complete pathological response rate(s) [ Time Frame: at time of surgical resection ]
    Fraction of patients who had a complete pathologic response of all patients who underwent surgery



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Histologically or cytologically proven pancreatic adenocarcinoma (subjects with endocrine or acinar pancreatic carcinoma are not eligible).
  • Patients must have stage III or IV pancreatic cancer (Cohort 1) or locally advanced pancreas cancer (LAPC), either borderline resectable pancreas cancer or locally advanced, unresectable pancreas cancer (Cohorts 2 and 3).
  • Patient must be eligible to undergo stereotactic body radiation therapy (SBRT) and have fiducial markers placed (any metal biliary stents are an acceptable alternative) (Cohorts 2-3).
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of M7824 and M9241 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
  • ECOG performance status of 0 to 1
  • Must have measurable disease, per RECIST 1.1.
  • Adequate hematological function defined by:

    • white blood cell (WBC) count greater than or equal to 3 times 10^9/L
    • with absolute neutrophil count (ANC) greater than or equal to 1.0 times 10^9/L,
    • lymphocyte count greater than or equal to 0.5 times 10^9/L,
    • platelet count greater than or equal to 100 times 10^9/L, and
    • Hgb greater than or equal to 9 g/dL (in absence of blood transfusion)
  • Adequate renal function defined by:

    • Creatinine OR Measured or calculated creatinine clearance (CrCl) (eGFR may also be used in place of CrCl)

      • < 1.75 x institution upper limit of normal OR
      • greater than or equal to 45 mL/min/1.73 m^2 for participant with creatinine levels greater than or equal to 1.75 X institutional ULN
    • Creatinine clearance (CrCl) or eGFR should be calculated per institutional standardu
  • Adequate hepatic function defined by:

    • a total bilirubin level less than or equal to 3 times ULN,
    • an AST level less than or equal to 5 times ULN,
    • ALT level less than or equal to 5 times ULN
  • Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
  • Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
  • The effects of the study treatment on the developing human fetus are unknown; thus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) at the study entry, for the duration of study treatment and up to 120 days after the last dose of the drug for males and up to 60 days for females. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patient must be able to understand and willing to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Treatment with any investigational agent within 28 days before ttreatment initiation.
  • Prior therapy with any antibody / drug targeting T cell coregulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody.
  • Anticancer treatment within designated period before treatment initiation including:

    • major surgical procedure (such as laparotomy) within 28 days
    • minor surgical procedure (such as biliary stenting) within 7 days
    • chemotherapy with published half-life known to be 72 hours within 7 days
    • chemotherapy with unpublished or half-life greater than 72 hours within 28 days
  • Receipt of any organ transplantation, including allogeneic stem-cell transplantation, except of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant)
  • Significant acute or chronic infections including tuberculosis (history of exposure or history of positive tuberculosis test; plus, presence of clinical symptoms, physical or radiographic findings)
  • Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent with the exceptions:

    • diabetes type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible;
    • subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses less than or equal to 10 mg of prednisone or equivalent per day;
    • administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation.
  • Known severe hypersensitivity reactions to monoclonal antibodies (Grade greater than or equal to 3 NCI-CTCAE v5.0), any history of anaphylaxis or history of uncontrolled asthma.
  • Known alcohol or drug abuse.
  • Clinically significant cardiovascular / cerebrovascular disease as follows: cerebral vascular accident / stroke (< 6 months prior to treatment initiation), myocardial infarction (< 6 months prior to treatment initiation), unstable angina, congestive heart failure (New York Heart Association Classification Class greater than or equal to II), or serious cardiac arrhythmia.
  • Administration of live vaccines within 21 days prior to treatment initiation.
  • HIV, HCV, HBV patients on antiviral drugs are excluded due to the absence of previous experience on combination of antiviral and this trial drugs and possible interaction.
  • Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically significant bleeding events, or other illness considered by the Investigator as high risk for investigational drug treatment.
  • Female patients who are pregnant or breastfeeding. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M7824 or M9241, breastfeeding should be discontinued.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04327986


Contacts
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Contact: Katherine O Lee-Wisdom, R.N. (240) 858-3525 katherine.lee-wisdom@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Udo Rudloff, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04327986    
Other Study ID Numbers: 200074
20-C-0074
First Posted: March 31, 2020    Key Record Dates
Last Update Posted: May 14, 2021
Last Verified: May 12, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Neoadjuvant therapy
Anti-Tumor Activity
Synergistic Anti-cancer Activity
Combining Immunotherapy and Radiation Therapy
Additional relevant MeSH terms:
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Pancreatic Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases