Clinical Trials /

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

NCT04327986

Description:

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.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 200074
  • SECONDARY ID: 20-C-0074
  • NCT ID: NCT04327986

Conditions

  • Histologically or Cytologically Confirmed Pancreatic Cancer
  • Unresectable or Borderline Resectable Pancreatic Cancer
  • Pancreatic Neoplasms
  • Pancreatic Cancer
  • Metastatic Pancreatic Cancer

Interventions

DrugSynonymsArms
M78241/Arm 1A
M92411/Arm 1A

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
1/Arm 1AExperimentalEscalating doses of M7824 / de-escalating doses of M9241
  • M7824
  • M9241
2/Arm 1BExperimentalDe-escalating doses of M9241 in combination with M7824 and SBRT
  • M7824
  • M9241
3/Arm 2ExperimentalRP2D of M7824 and M9241 in combination with SBRT
  • M7824
  • M9241

Eligibility 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) prior to 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 enrollment.

          -  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 enrollment 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 enrollment), myocardial infarction (<
             6 months prior to enrollment), 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 enrollment.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:To determine the PK of M7824 in combination with M9241
Time Frame:Cycle 1 Day 1
Safety Issue:
Description:PK interference of M7824 and M9241 based on AUC and Ctrough levels of M7824 alone at Cycle -1 Day 1 vs AUC and Ctrough levels Cycle 1 Day 1 when M7824 is administered with M9241
Measure:To assess overall survival (OS) in patients after completion of RT in combination with M9241 and M7824
Time Frame:death
Safety Issue:
Description:Kaplan-Meier curves
Measure:To asses progression-free survival (PFS) for all participants
Time Frame:at progression
Safety Issue:
Description:Kaplan-Meier curves
Measure:To asses progression-free survival (PFS) for participants who did not undergo surgical resection
Time Frame:at progression
Safety Issue:
Description:Kaplan-Meier curves
Measure: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
Safety Issue:
Description:Fraction of patients with LAPC who are able to undergo surgical resection after M7824 and M9241 in combination with SBRT treatment.
Measure: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
Safety Issue:
Description:Kaplan-Meier curves
Measure: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
Safety Issue:
Description:Fraction of patients who had a complete pathologic response of all patients who underwent surgery

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Neoadjuvant therapy
  • Anti-Tumor Activity
  • Synergistic Anti-cancer Activity
  • Combining Immunotherapy and Radiation Therapy

Last Updated

April 1, 2020