Maintenance Ipilimumab + Nivolumab Post Induction Chemotherapy + SBRT for First Line Treatment Stage IV Pancreatic Cancer

NCT05088889 | Unknown Phase 1

• 1 other identifier: CA184-604
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

In this study we aim to test the efficacy of a combined and novel approach including induction chemotherapy (per standard of care) followed by SBRT and maintenance ipililumab + nivolumab in the first line setting of stage IV PDAC. Study Hypothesis: Cytotoxic chemotherapy followed by hypofractionated radiotherapy will sensitize pancreatic cancer to immunotherapy consisting of combined PD-1 and CTLA4 blockade. We hypothesize that direct targeting of the pancreatic cancer cells by chemotherapy and hypofractionated radiotherapy is necessary for initial anti-tumor response. Furthermore, the combination of immunotherapy as a maintenance strategy will have profound anti-tumor efficacy in this setting. Implications of hypothesis:

• Improved response rate above historical controls
• Lengthened progression-free survival
• Improved overall-survival Exploratory Hypothesis: We hypothesize that baseline markers of immune activation such as Tumor Infiltrating Lymphocytes and CD8+ lymphocytes will correlate with response to ipililumab + nivolumab and that responders will have distinct tumor immune phenotype as determined by immunohistochemistry and gene expression profiling compared to nonresponders.

Conditions

Stage IV Pancreatic Cancer

Keywords

Pancreatic adenocarcinoma; SBRT (Stereotactic body radiation therapy); immunotherapy; RECIST1.1 (Response Evaluation Criteria in Solid Tumours V1.1)

Outcome Measures

Primary Outcomes (2)

• Objective tumor response rate1 (ORR1) in study patients, assessed by RECIST v1.1

  Proportion of subjects showing best overall response of complete response (CR) or partial response (PR)

  From first dose of SBRT until first progression, approximately 36 months.

• Objective tumor response rate 2 (ORR2) after first progression, assessed by RECIST v1.1

  Proportion of subjects with best overall response of CR or PR, in progressors who continue to receive low dose radiation and re-challenge nivolumab and ipilimumab

  From the date of low dose radiation until second progression, approximately 36 months

Secondary Outcomes (4)

• Progression free survival 1 (PFS 1) in stage 4 PDAC, assessed by RECIST 1.1

  From first dose of SBRT until first progression, approximately 36 months

• Objective tumor progression free survival 2 (PFS 2) in progressors, assessed by RECIST v1.1

  From the date of low dose radiation until second progression, approximately 36 months

• Median Overall survival (OS)

  From documented metastatic disease until death (or date of last documentation of being alive), approximately 36 months

• Incidence of Treatment-Emergent Adverse Events, as assessed by CTCAE version 5.0

  From day of subject's written consent until study termination, approximately 36 months

Other Outcomes (1)

• Assessment of disease biomarkers as a surrogates or predictors to response following administration of SBRT and immunotherapy: Exploratory

  5 years

Study Arms (1)

study arm

EXPERIMENTAL

Study treatments include SBRT (Stereotactic radiation therapy) to one primary/metastatic tumor (3 fractions of 8Gy) , and ipilimumab (1mg/kg every six weeks) + nivolumab (360mg every three weeks) . Every 8 weeks patients will be assessed for response; responders will continue ipilimumab + nivolumab until disease progression, non-responders will receive very low dose radiation (2Gy single fraction to metastatic lesions of choice) prior to continuing ipilimumab + nivolumab .

Drug: Nivolumab; Drug: ipilimumab; Radiation: Stereotactic body radiation therapy; Radiation: Low dose irradiation

Interventions

Nivolumab DRUG

Nivolumab administered IV over 30 minutes at a dose of 360mg every 3 weeks

study arm

ipilimumab DRUG

Ipilimumab administered IV over 30 minutes at 1 mg/kg every 6 weeks

study arm

Stereotactic body radiation therapy RADIATION

Three fractions of 8 Gy, treated on alternate days

Also known as: SBRT

study arm

Low dose irradiation RADIATION

a single fraction of 2Gy will be given to the metastatic lesions at first progression

study arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provide written informed consent and be between the ages of 18 and up.
• Metastatic histology proven adenocarcinoma of the pancreas. If patient has primary resected tumor, tumor recurrence needs to \>12 months after last adjuvant chemotherapy.
• ECOG performance status 0-1.
• Life expectancy of \>= 3 months.
• If female and of child-bearing potential, have a negative serum pregnancy test during screening.
• Agree to use of a barrier method of contraception if sexually active (both men and women) from the time of administration of the first treatment and for at least 5 months after treatment.
• Have PT - INR \< 1.5, WBC \> 2000/μL absolute neutrophil count (ANC) \> 1500 x 103 cells/ μL, platelets ≥ 100,000/ μL, and hemoglobin \>= 9 mg/dL Serum creatinine \< 1.5 x ULN, unless creatinine clearance ≥ 40 mL/min (measured or calculated using the Cockroft-Gault formula) AST/ALT: \< 3.0 x ULN Total bilirubin \< 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of \< 3.0x ULN).
• A disease lesion, including primary pancreas lung/liver/peritoneal/bone /lynph nodes, that is suitable for SBRT as deemed by the investigator.
• Screening procedures completed within 4 weeks of starting treatment.
• Availability of at least 1 measurable lesion not previously irradiated that is not planned to be irradiated with SBRT during the study and measurable as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Patient received minimum of 4 cycles of first-line chemotherapy of induction chemotherapy per investigator's decision without progression.
• Adjuvant treatment is allowed if ≥ 12 months has passed since last adjuvant treatment.
• Fresh biopsy specimens are required unless biopsy deemed unsafe by investigator.

You may not qualify if:

• Clinically significant pancreatitis within 8 weeks of treatment.
• Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy for the entire study period and for up to 5 months after the study are excluded.
• A medical condition or any intercurrent medical illness or other medical condition that would in the judgment of the investigator compromise patient safety or the objectives of the study.
• Have participated in any therapeutic research study within the last 4 weeks.
• Known medical condition that predisposes to radiation toxicity (e.g. scleroderma)
• Has a known MSI-H phenotype or a known MMR deficiency.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment.
• Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with type I diabetes mellitus, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Subjects that require intermittent use of bronchodilators or local steroids, e.g., inhaled or topical steroids, at a dose of less than the equivalent of 10mg prednisone daily, would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study.
• Has evidence of interstitial lung disease or active, non-infectious pneumonitis
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial (chronic pain management medications should not exclude study participation).

Sponsors & Collaborators

• Sheba Medical Center: lead
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Sheba Medical Centre

Ramat Gan, Israel

RECRUITING

Related Publications (5)

• Demaria S, Golden EB, Formenti SC. Role of Local Radiation Therapy in Cancer Immunotherapy. JAMA Oncol. 2015 Dec;1(9):1325-32. doi: 10.1001/jamaoncol.2015.2756.

  PMID: 26270858 BACKGROUND

• Menon H, Chen D, Ramapriyan R, Verma V, Barsoumian HB, Cushman TR, Younes AI, Cortez MA, Erasmus JJ, de Groot P, Carter BW, Hong DS, Glitza IC, Ferrarotto R, Altan M, Diab A, Chun SG, Heymach JV, Tang C, Nguyen QN, Welsh JW. Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy. J Immunother Cancer. 2019 Sep 4;7(1):237. doi: 10.1186/s40425-019-0718-6.

  PMID: 31484556 BACKGROUND

• Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33. doi: 10.1056/NEJMoa1302369. Epub 2013 Jun 2.

  PMID: 23724867 BACKGROUND

• Milas L, Mason KA, Ariga H, Hunter N, Neal R, Valdecanas D, Krieg AM, Whisnant JK. CpG oligodeoxynucleotide enhances tumor response to radiation. Cancer Res. 2004 Aug 1;64(15):5074-7. doi: 10.1158/0008-5472.CAN-04-0926.

  PMID: 15289307 BACKGROUND

• Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J Natl Cancer Inst. 2013 Feb 20;105(4):256-65. doi: 10.1093/jnci/djs629. Epub 2013 Jan 4.

  PMID: 23291374 BACKGROUND

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

Nivolumab; Ipilimumab; Radiosurgery; Radiation

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Physical Phenomena

Study Officials

• Talia Golan, Prof.

  Shaba Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Talia Golan, Prof.

CONTACT

972545774869; Talia.Golan@sheba.health.gov.il

Tali Aviv

CONTACT

972544557545; Tali.Aviv@sheba.health.gov.il

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical diractor of phase 1 clinical trials unit and Sheba pancreatic cancer program

Study Record Dates

• First Submitted: June 22, 2021
• First Posted: October 22, 2021
• Study Start: January 25, 2022
• Primary Completion: July 1, 2024
• Study Completion: July 1, 2024
• Last Updated: November 28, 2023

Record last verified: 2023-11

Locations

IL (1)