Clinical Trials /

Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer

NCT02311361

Description:

Background: - Stereotactic body radiation therapy (SBRT) is used to treat cancer. It is a way of giving very focused beams of radiation to tumors. Researchers think that the drugs being used in this study might work better when combined with SBRT in people with pancreatic cancer. Objective: - To study the safety and effectiveness of MEDI4736 and/or tremelimumab with SBRT. Eligibility: - People 18 and older who have pancreatic cancer that has not responded or to chemotherapy. They must be candidates for radiation but not resection. Design: - Participants will be screened with medical history and physical exam. They will have blood tests. Their tumor will be measured using computerized tomography (CT) or magnetic resonance imaging (MRI). - Participants will have their tumor biopsied with a needle. They will have also have a biopsy after cycle 1. - Participants will get 1 or 2 drugs in combination with the SBRT. - For MEDI4736, the duration of each cycle will be 28-days. Participants will get the drug through an intravenous (IV) infusion twice in each cycle (Days 1 and 15). - For tremelimumab, the duration of the first 6 cycles will each last 28 days. Then the duration of the last 3 cycles will change to 12 weeks. Participants will get the drug through an IV once in each cycle. - All participants will have SBRT. Some will get 1 dose of radiation and some will get 5. CT scans will map their tumor. - Participants will have medical history, physical exam, and blood tests in each cycle. They will have a CT scan or MRI every 8 weeks. Cycles will continue for up to 12 months. - Participants will be contacted yearly for follow-up.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Immune Checkpoint Inhibition (Tremelimumab and/or MEDI4736) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer
  • Official Title: A Pilot Study of Immune Checkpoint Inhibition (Durvalumab With or Without Tremelimumab) in Combination With Radiation Therapy in Patients With Unresectable Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: 150027
  • SECONDARY ID: 15-C-0027
  • NCT ID: NCT02311361

Conditions

  • Pancreatic Neoplasms
  • Pancreatic Cancer
  • Cancer of Pancreas
  • Cancer of the Pancreas
  • Pancreas Cancer

Interventions

DrugSynonymsArms
Durvalumab1/A1
Tremelimumab4/B2 (was removed with Amendment A)

Purpose

Background: - Stereotactic body radiation therapy (SBRT) is used to treat cancer. It is a way of giving very focused beams of radiation to tumors. Researchers think that the drugs being used in this study might work better when combined with SBRT in people with pancreatic cancer. Objective: - To study the safety and effectiveness of MEDI4736 and/or tremelimumab with SBRT. Eligibility: - People 18 and older who have pancreatic cancer that has not responded or to chemotherapy. They must be candidates for radiation but not resection. Design: - Participants will be screened with medical history and physical exam. They will have blood tests. Their tumor will be measured using computerized tomography (CT) or magnetic resonance imaging (MRI). - Participants will have their tumor biopsied with a needle. They will have also have a biopsy after cycle 1. - Participants will get 1 or 2 drugs in combination with the SBRT. - For MEDI4736, the duration of each cycle will be 28-days. Participants will get the drug through an intravenous (IV) infusion twice in each cycle (Days 1 and 15). - For tremelimumab, the duration of the first 6 cycles will each last 28 days. Then the duration of the last 3 cycles will change to 12 weeks. Participants will get the drug through an IV once in each cycle. - All participants will have SBRT. Some will get 1 dose of radiation and some will get 5. CT scans will map their tumor. - Participants will have medical history, physical exam, and blood tests in each cycle. They will have a CT scan or MRI every 8 weeks. Cycles will continue for up to 12 months. - Participants will be contacted yearly for follow-up.

Detailed Description

      Background:

      Tremelimumab is a monoclonal antibody against CTLA4. Anti-CTLA4 therapy has been shown to
      enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T
      cells.

      Durvalumab is a human monoclonal antibody directed against PD-L1. Blockage of ligation
      between PD-L1 and PD1 induces local immune activation and prevent anergy and exhaustion of
      effectors T-cells.

      Several studies have documented an increase in peripheral antitumor immunity following
      radiation. This effect is evidently too weak to be clinically relevant, but has the potential
      to be boosted by immune modulation.

      The underlying hypothesis of this study is that the effect of Immune Checkpoint inhibitor
      (Durvalumab with or without Tremelimumab) treatment can be enhanced by radiation in patients
      with advanced pancreatic carcinoma.

      Objective:

      To determine the safety, tolerability and feasibility of immune checkpoint inhibition
      [comprising either Durvalumab alone, or combined Durvalumab and Tremelimumab] in combination
      with stereotactic body radiation therapy (SBRT) in patients with unresectable pancreatic
      cancer.

      Eligibility:

      Histologically confirmed metastatic pancreatic cancer with primary in-situ (or
      locally-recurrent) with at least 1 measurable metastatic lesion by RECIST 1.1 criteria and
      accessible for biopsy. There is no limit to the number of prior chemotherapy regimens
      received.

      Patients must be greater than or equal to 18 years of age and have a performance status
      (ECOG) less than or equal to 1

      Life expectancy of greater than 3 months.

      Acceptable organ and bone marrow function.

      Patients must not have had standard of care chemotherapy, radiotherapy, or major surgery
      within the last 2 weeks prior to entering the study. For recent experimental therapies a 28
      day period of time must have elapsed before commencing protocol treatment.

      No active or prior documented autoimmune or inflammatory disorders (including inflammatory
      bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable
      bowel disease; Wegner syndrome; Hashimoto syndrome; Graves disease; rheumatoid arthritis,
      hypophysitis, uveitis, etc.) within the past 3 years prior to the start of treatment.

      No active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel
      disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated
      with diarrhea. No active or history of systemic lupus erythematosus, Wegener s
      granulomatosis.

      Design:

      Subjects will be assigned to 4 arms

      Anti-PDL1 (Durvalumab) in combination with radiation (8 Gy in fraction)

      - Anti-PDL1 (Durvalumab) in combination with radiation (5 Gy in 5 fractions)

      Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (8 Gy in 1
      fractions)

      - Anti-PDL1 (Durvalumab) and anti-CTLA4 (Tremelimumab) in combination with radiation (5 Gy in
      5 fractions).
    

Trial Arms

NameTypeDescriptionInterventions
1/A1ExperimentalDurvalumab + 8Gy in 1 fraction
  • Durvalumab
2/A2ExperimentalDurvalumab +5 Gy in 5 fractions
  • Durvalumab
3/B1 (was removed with Amendment A)ExperimentalTremelimumab + 8 Gy in 1 fraction
  • Tremelimumab
4/B2 (was removed with Amendment A)ExperimentalTremelimumab + 5 Gy in 5 fractions
  • Tremelimumab
5/C1ExperimentalDurvalumab +Tremelimumab + 8 Gy in 1 fraction
  • Durvalumab
  • Tremelimumab
6/C2ExperimentalDurvalumab +Tremelimumab +5 Gy in 5 fractions
  • Durvalumab
  • Tremelimumab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histopathological confirmation of pancreatic adenocarcinoma prior
             to entering this study by the Laboratory of Pathology of the NCI to entering this
             study by the Laboratory of Pathology of the NCI prior to entering this study

          -  Patients must have disease that is not amenable to potentially curative resection.
             Primary in-situ (or locally-recurrent) tumor must be present and, in the opinion of
             radiation oncology, be amenable to radiation therapy as planned in the protocol. Each
             case will be discussed at GI tumor board with multidisciplinary team.

          -  Patients must have at least 1 measurable metastatic lesion by RECIST1.1 criteria.

          -  There is no limit to the number of prior chemotherapy regimens received. Patients must
             have received at least one line of prior systemic chemotherapy for advanced
             unresectable and/or metastatic disease.

          -  Age greater than or equal to 18 years

          -  Life expectancy of greater than 3 months.

          -  ECOG performance status 0-1

          -  Patients must have normal organ and marrow function as defined below:

               -  absolute neutrophil count - > 1,000/mcL

               -  Platelets - greater than or equal to 100,000/mcL

               -  total bilirubin - Bili should be less than or equal to 2 x ULN (patients with
                  Gilbert's Syndrome must have a total bilirubin less than 3.0 mg/dL)

               -  serum albumin - greater than or equal 2.5 g/dL

        Patients are eligible with ALT or AST up to 3 x ULN. (up to 5 x ULN if liver metastases
        present)

        --Creatinine - < 2X institution upper limit of normal

        OR

        --creatinine clearance - >45 mL/min/1.73 m(2), for patients with creatinine levels above
        institutional normal

          -  Patients must have recovered from any acute toxicity related to prior therapy,
             including surgery. Toxicity should be less than or equal to grade 1 or returned to
             baseline.

          -  Patient must be able to understand and willing to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          -  Malignant ascites that is clinically detectable by physical examination or is
             symptomatic. Evidence of radiographic ascites that is not clinically significant will
             not be an exclusion criterion.

          -  Any prior Grade greater than or equal to 3 imAE while receiving immunotherapy,
             including anti-CTLA4 treatment, or any unresolved imAE > Grade 1. Note: Active or
             history of vitiligo will not be a basis for exclusion.

          -  Patients must not have had standard of care chemotherapy, radiotherapy, or major
             surgery within the last 2 weeks prior to entering the study. Note: Local surgeries for
             isolated lesions for palliative intent are acceptable. For recent experimental
             therapies a 28 day period of time must have elapsed before commencing protocol
             treatment.

          -  Patients with known brain metastases will be excluded from this clinical trial because
             of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

          -  Uncontrolled intercurrent illness, including, but not limited to, ongoing or active
             infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled
             hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease,
             or psychiatric illness/social situations that would limit compliance with study
             requirement, substantially increase risk of incurring adverse events from MEDI4736 or
             tremelimumab, or compromise the ability of the subject to give written informed
             consent.

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease, diverticulitis with the exception of diverticulosis,
             celiac disease, irritable bowel disease; Wegner syndrome; Hashimoto syndrome; Graves
             disease; rheumatoid arthritis, hypophysitis, uveitis, etc.) within the past 3 years
             prior to the start of treatment. The following are exceptions to this criterion:

               -  Subjects with vitiligo or alopecia

               -  Requirement for intermittent use of bronchodilators or local steroid injections

               -  Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
                  replacement, or psoriasis not requiring systemic treatment

          -  History of primary immunodeficiency or history of active tuberculosis. Note: Latent
             tuberculosis will not be a basis for exclusion.

          -  Diverticulitis (either active or history of) within the past 2 years. Note that
             diverticulosis is permitted.

          -  Dementia or significantly altered mental status that would prohibit the understanding
             or rendering of Information and Consent and compliance with the requirements of the
             protocol.

          -  True positive test results for hepatitis A (IgM positive). Subjects with a history of
             hepatitis A with IgG blood test are not excluded. True positive test results hepatitis
             B, or C infection.

          -  Active or history of inflammatory bowel disease (colitis, Crohn s), irritable bowel
             disease, celiac disease, or other serious, chronic, gastrointestinal conditions
             associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener
             s granulomatosis.

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of MEDI4736 and tremelimumab. The following are exceptions to this criterion:

               -  Intranasal, inhaled, and topical steroids

               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                  prednisone or equivalent

               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan
                  premedication)

          -  History of sarcoidosis syndrome.

          -  Patients should not be vaccinated with live attenuated vaccines within 1 month of
             starting Tremelimumab and MEDI4736 treatment. Subjects, if enrolled, should not
             receive live vaccine during the study and 180 days after the last dose of both drugs.

          -  HIV-positive patients receiving anti-retroviral therapy are excluded from this study
             due to the possibility of pharmacokinetic interactions between antiretroviral
             medications and Tremelimumab or MEDI4736. HIV positive patients not receiving
             antiretroviral therapy are excluded due to the possibility that Tremelimumab or
             MEDI4736 may worsen their condition and the likelihood that the underlying condition
             may obscure the attribution of adverse events.

          -  History of hypersensitivity reaction to human or mouse antibody products.

          -  Pregnancy and breast feeding are exclusion factors. The effects of Tremelimumab and
             MEDI4736 on the developing human fetus are unknown. Enrolled patients must agree to
             use adequate contraception (hormonal or barrier method of birth control; abstinence)
             prior to study entry, the duration of study participation and 180 days (female
             patients) or 90 days (male patients) after the end of the treatment. In addition male
             patients must refrain from sperm donation for 90 days after the final dose of
             investigational product. Female patients must refrain from egg cell donation for 180
             days after the final dose of investigational product. 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.

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of the investigational product or interpretation of subject safety or study
             results.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety
Time Frame:30 days after treatment
Safety Issue:
Description:List of adverse event frequency

Secondary Outcome Measures

Measure:plasma pharmacokinetic (PK)
Time Frame:30 days after treatment
Safety Issue:
Description:Drug level in blood
Measure:6-month overall survival rate
Time Frame:6 month
Safety Issue:
Description:Median amount of time subject survives after therapy
Measure:overall survival
Time Frame:Death
Safety Issue:
Description:Median amount of time subject survives after therapy
Measure:Overall response rate
Time Frame:At tumor progression
Safety Issue:
Description:Proportion of patients whose tumors shrunk after therapy
Measure:Progression free survival
Time Frame:At progression
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Anti-PDL1
  • Anti-CTLA4
  • Streostatic Body Radiation Therapy (SBRT)
  • Monoclonal Antibody
  • Antitumor Immunity

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