Clinical trial NCT04327986: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Histologically or Cytologically Confirmed Pancreatic Cancer
Unresectable or Borderline Resectable Pancreatic Cancer
Pancreatic Neoplasms
Pancreatic Cancer
Metastatic Pancreatic Cancer
Keywords: Neoadjuvant therapy
Anti-Tumor Activity
Synergistic Anti-cancer Activity
Combining Immunotherapy and Radiation Therapy
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2020-03-31
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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 Bintrafusp Alfa (M7824), NHS-IL12 (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.

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.
* Bintrafusp alfa (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 NHS-IL12 (M9241) immunocytokine is composed of 2 interleukin-12 (IL-12) heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded deoxyribonucleic acid (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 stereotactic body radiotherapy (SBRT) as neoadjuvant/perioperative treatment in subjects with pancreas cancer.
* To determine a preliminary estimate of efficacy as best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors (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.

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 bintrafusp alfa (M7824) and NHS-IL12 (M9241) in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Must have measurable disease, per Response Evaluation Criteria in Solid Tumors (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
  * Hemoglobin (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) (estimated glomerular filtration rate (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 upper limit of normal (ULN)
  * Creatinine clearance (CrCl) or eGFR should be calculated per institutional standard
* Adequate hepatic function defined by:

  * a total bilirubin level less than or equal to 3 times ULN,
  * an aspartate aminotransferase (AST) level less than or equal to 5 times ULN,
  * alanine aminotransferase (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 treatment initiation.
* Prior therapy with any antibody / drug targeting T cell coregulatory proteins (immune checkpoints) such as anti-Programmed cell death protein 1 (PD-1), anti-Programmed death-ligand 1 (PD-L1), or anti-cluster of differentiation 152 (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 National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (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 30 days prior to treatment initiation.
* Human immunodeficiency virus (HIV), hepatitis C virus (HCV), hepatitis B virus (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.
* Subjects unwilling to accept blood products as medically indicated.
* 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.

Primary outcomes:
measure: Recommended Phase 2 Dose (RP2D) of NHS-IL12 (M9241) Given With Bintrafusp Alfa (M7824) in Combination With Stereotactic Body Radiation Therapy (SBRT) as Neoadjuvant / Perioperative Treatment in Participants With Pancreas Cancer
timeFrame: First 28 days of treatment
measure: Number of Participants With ≥Grade 3 Toxicities Possibly, Probably, or Definitely Related to Treatment of Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT)
timeFrame: Date treatment consent signed to date off study, approximately 4 months and 13 days.
measure: Best Overall Response (BOR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) of Bintrafusp Alfa (M7824) & NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy in Participants With Locally Advanced Pancreas Cancer
timeFrame: time measurement criteria are met for complete response or partial response until the first date that recurrent or progressive disease is objectively documented
Secondary outcomes:
measure: Overall Survival (OS) in Participants After Completion of Radiation Therapy (RT) in Combination With NHS-IL12 (M9241) and Bintrafusp Alfa (M7824)
timeFrame: date of on-study to the date of death from any cause or last follow
measure: Progression-free Survival (PFS) for All Participants
timeFrame: Time interval from start to treatment to disease progression, an average of 4 months.
measure: Progression-free Survival (PFS) for Participants Who Did Not Undergo Surgical Resection
timeFrame: time interval from start of treatment to documented evidence of disease progression
measure: Fraction of Participants With Locally Advanced, Non-metastatic Pancreas Cancer (LAPC) Who Are Able to Undergo Surgical Resection After Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT) Treatment
timeFrame: At time of surgical resection
measure: Time-to-recurrence of the Disease For Participants Who Underwent Surgical Resection After Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT) Treatment
timeFrame: At disease recurrence after surgical resection
measure: Complete Pathological Response Rate(s) For Participants Who Underwent Surgical Resection After Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT) Treatment
timeFrame: At time of surgical resection
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).
timeFrame: Date treatment consent signed to date off study, approximately 4 months and 13 days.
measure: Number of Participants With a Dose-limiting Toxicity (DLT)
timeFrame: First 28 days of treatment
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Udo Rudloff, M.D.
role: PRINCIPAL_INVESTIGATOR
References: