Clinical Trials /

Durvalumab and Tremelimumab With or Without High or Low-Dose Radiation Therapy in Treating Patients With Metastatic Colorectal or Non-small Cell Lung Cancer

NCT02888743

Description:

This randomized phase II trial studies the side effects of durvalumab and tremelimumab and to see how well they work with or without high or low-dose radiation therapy in treating patients with colorectal or non-small cell lung cancer that has spread to other parts of the body. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving durvalumab and tremelimumab with radiation therapy may work better in treating patients with colorectal or non-small cell lung cancer.

Related Conditions:
  • Colorectal Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Durvalumab and Tremelimumab With or Without High or Low-Dose Radiation Therapy in Treating Patients With Metastatic Colorectal or Non-small Cell Lung Cancer
  • Official Title: A Phase 2 Study of MEDI4736 (Durvalumab) and Tremelimumab Alone or in Combination With High or Low-Dose Radiation in Metastatic Colorectal and NSCLC

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01325
  • SECONDARY ID: NCI-2016-01325
  • SECONDARY ID: 10021
  • SECONDARY ID: 10021
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT02888743

Conditions

  • Microsatellite Stable
  • Stage IV Colorectal Cancer AJCC v7
  • Stage IV Non-Small Cell Lung Cancer AJCC v7
  • Stage IVA Colorectal Cancer AJCC v7
  • Stage IVB Colorectal Cancer AJCC v7

Interventions

DrugSynonymsArms
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm A (tremelimumab, durvalumab)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabArm A (tremelimumab, durvalumab)

Purpose

This randomized phase II trial studies the side effects of durvalumab and tremelimumab and to see how well they work with or without high or low-dose radiation therapy in treating patients with colorectal or non-small cell lung cancer that has spread to other parts of the body. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving durvalumab and tremelimumab with radiation therapy may work better in treating patients with colorectal or non-small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess safety and tolerability of combined checkpoint blockade with MEDI4736
      (durvalumab) and tremelimumab alone or with high or low-dose radiation in non-small cell lung
      cancer (NSCLC). (NSCLC Cohort) II. To compare the overall response (excluding the irradiated
      lesion[s]) between combined checkpoint blockade with MEDI4736 and tremelimumab alone or
      combined checkpoint blockade with low or high dose radiation. (NSCLC Cohort) III. To assess
      safety and tolerability of combined checkpoint blockade with MEDI4736 and tremelimumab with
      high or low-dose radiation. (Colorectal Cohort) IV. To determine the overall response rate
      (excluding the irradiated lesion[s]) with combined checkpoint blockade with MEDI4736 and
      tremelimumab with either low or high dose radiation. (Colorectal Cohort)

      SECONDARY OBJECTIVES:

      I. To estimate median progression-free survival and overall survival. (NSCLC Cohort) II. To
      determine local control within the irradiated field(s) and abscopal response rates. (NSCLC
      Cohort) III. To evaluate associations between PD-L1 expression as well as levels of
      infiltrating CD3+, CD8+ T-cells and overall response. (NSCLC Cohort) IV. To explore changes
      in PD-L1 expression, circulating T-cell populations, T-cell infiltration, ribonucleic acid
      (RNA) expression, spatial relationship of immune markers, and mutational burden as a result
      of low or high dose radiation. (NSCLC Cohort) V. To estimate median progression-free survival
      and overall survival. (Colorectal Cohort) VI. To determine local control within the
      irradiated field and abscopal response rates. (Colorectal Cohort) VII. To evaluate
      associations between PD-L1 expression as well as levels of infiltrating CD3+ CD8+ T-cells and
      overall response. (Colorectal Cohort) VIII. To evaluate changes between PD-L1 expression as
      well as levels of infiltrating CD3+, CD8+ T-cells induced by targeted low or high dose
      radiation. (Colorectal Cohort) IX. To explore changes in circulating T-cell populations,
      T-cell infiltration, RNA expression, spatial relationship of immune markers, and mutational
      burden as a result of low or high dose radiation.

      OUTLINE: Patients with NSCLC are randomized to Arm A, B, or C. Patients with colorectal
      cancer are randomized to Arm B or C.

      COHORT 1: Patients with NSCLC are randomized to 1 of 3 arms.

      ARM A: Patients receive tremelimumab intravenously (IV) and durvalumab IV over 60 minutes
      every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable
      toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination
      dose for up to 9 additional doses.

      ARM B: Patients receive tremelimumab and durvalumab and as in Arm A. Beginning at week 2,
      patients receive high dose radiation therapy once per day (QD) over 10 days for up to 3
      fractions.

      ARM C: Patients receive tremelimumab and durvalumab and as in Arm A. Beginning at week 2,
      patients receive low dose radiation therapy every 6 hours twice per day (BID) on weeks 2, 6,
      10 and 14.

      After completion of study treatment, patients are followed for up to 12 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (tremelimumab, durvalumab)ExperimentalPatients receive tremelimumab IV and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses.
    Arm B (tremelimumab, Durvalumab, RT)ExperimentalPatients receive tremelimumab and durvalumab and as in Arm A. Beginning at week 2, patients receive high dose radiation therapy QD over 10 days for up to 3 fractions.
      Arm C (tremelimumab, durvalumab, and RT)ExperimentalPatients receive tremelimumab and durvalumab and as in Arm A. Beginning at week 2, patients receive low dose radiation therapy every 6 hours BID on weeks 2, 6, 10 and 14.

        Eligibility Criteria

                Inclusion Criteria:
        
                  -  Patients must have histologically or cytologically confirmed non-small cell lung
                     cancer (cohort 1) or colorectal cancer (cohort 2)
        
                  -  Patients must have measurable disease, defined as at least one lesion that can be
                     accurately measured in at least one dimension (longest diameter to be recorded for
                     non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
                     conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
                     scan, magnetic resonance imaging (MRI), or calipers by clinical exam
        
                  -  Patients in both cohorts must have progressive disease following prior therapy;
                     specifically:
        
                       -  Cohort 1 (NSCLC): Patients must have evidence of radiologic or clinical disease
                          progression during previous treatment with systemic PD-1 directed therapy and/or
                          have been deemed not to derive clinical benefit from PD-1 directed treatment;
                          this includes patients who demonstrated an initial response and subsequent
                          progression; no prior treatment with chemotherapy or targeted agents are
                          required; intervening therapy is allowed between previous PD-1 directed treatment
                          and there is no required interval from prior PD-1 treatment required; PD-1
                          directed treatment includes treatment with antibodies targeting the PD-1 receptor
                          such as pembrolizumab or nivolumab, as well as PD-L1 targeted antibodies such as
                          MEDI4736 (durvalumab), atezolizumab and avelumab; these agents may have been
                          administered as part of a clinical trial
        
                       -  Cohort 2 (colorectal cancer): Patients must have progressed on first-line
                          chemotherapy
        
                  -  At least 21 days must have elapsed from prior therapy (chemotherapy or radiation)
        
                  -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)
                     and life expectancy greater than 6 months; furthermore, enrollment of patients with
                     greater than 10 measurable lesions is discouraged
        
                  -  Patients must have normal organ and marrow function independent of transfusion for at
                     least 7 days prior to screening and independent of growth factor support for at least
                     14 days prior to screening
        
                  -  Hemoglobin (Hgb) >= 9 g/dl
        
                  -  Absolute neutrophil count >= 1,500/mcL
        
                  -  Platelets >= 100,000/mcL
        
                  -  Total bilirubin =< 1.5 x normal institutional limits; this will not apply to patients
                     with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia
                     [predominantly unconjugated bilirubin] in the absence of evidence of hemolysis or
                     hepatic pathology), who will be allowed in consultation with their physician
        
                  -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
                     [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
                     = < 2.5 x institutional upper limit of normal; for patients with hepatic metastases,
                     ALT and AST =< 5 x ULT
        
                  -  Measured creatinine clearance (CL) > 40 mL/min OR calculated creatinine clearance (CL)
                     >40 mL/min as determined by Cockcroft-Gault (using actual body weight)
        
                  -  Patients must have at least one lesion that has not previously been irradiated (and is
                     not within a previously radiated field) and for which palliative radiation is
                     potentially indicated and could be safely delivered at the radiation doses specified
                     in this protocol; this lesion must not be the only measurable lesion so that it is
                     still possible to determine the response rate outside of the radiation treatment
                     field; this lesion must not be within the central nervous system (CNS) (brain or
                     spinal cord) or requiring urgent or emergent palliative radiation given the timing of
                     radiation specified on this protocol; furthermore, this lesion:
        
                       -  For cohort 1 (NSCLC cohort) - the lesion to be irradiated must be in the lung,
                          lymph nodes of the neck, adrenal gland or liver
        
                       -  For cohort 2 (colorectal cohort) - the lesion to be irradiated must be in the
                          liver
        
                  -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for
                     female pre-menopausal patients is required; women will be considered post-menopausal
                     if they have been amenorrheic for 12 months without an alternative medical cause; the
                     following age-specific requirements apply:
        
                       -  Women < 50 years of age would be considered post-menopausal if they have been
                          amenorrheic for 12 months or more following cessation of exogenous hormonal
                          treatments and if they have luteinizing hormone and follicle stimulating hormone
                          levels in the post-menopausal range for the institution or underwent surgical
                          sterilization (bilateral oophorectomy or hysterectomy)
        
                       -  Women >= 50 years of age would be considered post-menopausal if they have been
                          amenorrheic for 12 months or more following cessation of all exogenous hormonal
                          treatments, had radiation-induced oophorectomy with last menses > 1 year ago, had
                          chemotherapy-induced menopause with > 1 year interval since last menses, or
                          underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
        
                  -  Females of childbearing potential who are sexually active with a non sterilized male
                     partner must use at least 1 highly effective method of contraception from the time of
                     screening and must agree to continue using such precautions for 180 days after the
                     last dose of durvalumab + tremelimumab combination therapy or 90 days after the last
                     dose of durvalumab monotherapy; non-sterilised male partners of a female patient must
                     use male condom plus spermicide throughout this period; cessation of birth control
                     after this point should be discussed with a responsible physician; not engaging in
                     sexual activity for the total duration of the drug treatment and the drug washout
                     period is an acceptable practice; however, periodic abstinence, the rhythm method, and
                     the withdrawal method are not acceptable methods of birth control; female patients
                     should also refrain from breastfeeding throughout this period
        
                  -  Non-sterilized males who are sexually active with a female partner of childbearing
                     potential must use a male condom plus spermicide from screening through 180 days after
                     receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days
                     after receipt of the final dose of durvalumab monotherapy; not engaging in sexual
                     activity is an acceptable practice; however, occasional abstinence, the rhythm method,
                     and the withdrawal method are not acceptable methods of contraception; male patients
                     should refrain from sperm donation throughout this period
        
                  -  Female partners (of childbearing potential) of male patients must also use a highly
                     effective method of contraception throughout this period
        
                  -  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
        
                  -  Ability to understand and the willingness to sign a written informed consent document
        
                  -  Body weight > 30 kg
        
                  -  Cohort 1 (NSCLC cohort)
        
                       -  Ability to undergo a fresh tumor biopsy for the purpose of screening for this
                          clinical trial (including able and willing to give valid written consent) to
                          ability or to provide an available archival tumor sample taken less than 3 months
                          prior to study enrollment (and not obtained prior to progression on a PD-1/PD-L1
                          inhibitor) if a fresh tumor biopsy is not feasible with an acceptable clinical
                          risk; tumor lesions used for fresh biopsies should be the same lesions to be
                          irradiated when possible and should not be the same lesions used as Response
                          Evaluation Criteria in Solid Tumors (RECIST) target lesions, unless there are no
                          other lesions accessible; additional, optional archival tumor tissue is also
                          requested from before the prior PD-1 directed therapy
        
                  -  Cohort 2 (colorectal cohort)
        
                       -  Ability to undergo a fresh tumor biopsy for the purpose of screening for this
                          clinical trial (including able and willing to give valid written consent) to
                          ability or to provide an available archival tumor sample taken less than 3 months
                          prior to study enrollment if a fresh tumor biopsy is not feasible with an
                          acceptable clinical risk; tumor lesions used for fresh biopsies should be the
                          same lesions to be irradiated when possible and should not be the same lesions
                          used as RECIST target lesions, unless there are no other lesions accessible
        
                       -  Microsatellite stable (MSS) tumor as documented by either:
        
                            -  Immunohistochemistry (IHC) testing that does not suggest loss of MLH-1,
                               MSH-2, PMS2 or MSH6
        
                            -  Polymerase chain reaction (PCR) testing that does not suggest microsatellite
                               instability (MSI)
        
                Exclusion Criteria:
        
                  -  Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
                     nitrosoureas or mitomycin C) prior to entering the study
        
                  -  Receipt of prior radiotherapy or condition for any reason that would contribute
                     radiation dose that would exceed tolerance of normal tissues, at the discretion of the
                     treating physician
        
                  -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
                     (i.e., have residual toxicities > grade 1)
        
                  -  Patients who are receiving any other investigational agents
        
                  -  Patients with untreated brain metastases, spinal cord compression, or leptomeningeal
                     carcinomatosis should be excluded from this clinical trial; patients whose brain
                     metastases have been treated may participate provided they show radiographic stability
                     (defined as 2 brain images, both of which are obtained after treatment to the brain
                     metastases; these imaging scans should both be obtained at least four weeks apart and
                     show no evidence of intracranial progression); in addition, any neurologic symptoms
                     that developed either as a result of the brain metastases or their treatment must have
                     resolved or be stable either, without the use of steroids, or are stable on a steroid
                     dose of =< 10 mg/day of prednisone or its equivalent (and anti-convulsants) for at
                     least 14 days prior to the start of treatment
        
                  -  History of allergic reactions attributed to compounds of similar chemical or biologic
                     composition to tremelimumab and MEDI4736 or previous toxicity attributed to MEDI4736
                     or other PD-1 or PD-L1 directed therapy that led to drug discontinuation
        
                  -  Prior exposure to immune-mediated therapy, except for anti-PD-1 or anti-PD-L1 therapy
                     in NSCLC patients; this includes anti-CTLA-4 agents (prior treatment with these agents
                     is NOT allowed in either cohort) and, excludes therapeutic anticancer vaccines,
                     excluding therapeutic anticancer vaccines; exposure to other investigational agents
                     may be permitted after discussion with the study principal investigator (PI)
        
                  -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
                     infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
                     arrhythmia, or psychiatric illness/social situations that would limit compliance with
                     study requirements
        
                  -  Pregnant women are excluded from this study; breastfeeding should be discontinued if
                     the mother is treated with MEDI4736 (durvalumab), tremelimumab and radiation
        
                  -  Female patients who are pregnant or breastfeeding or male or female patients of
                     reproductive potential who are not willing to employ effective birth control from
                     screening to 90 days after the last dose of durvalumab monotherapy or 180 days after
                     the last dose of durvalumab + tremelimumab combination therapy, whichever is later
        
                  -  Human immunodeficiency virus (HIV)-positive patients are ineligible; appropriate
                     studies will be undertaken in patients receiving combination antiretroviral therapy
                     when indicated
        
                  -  Any concurrent chemotherapy, immune therapy, biologic, hormonal therapy for cancer
                     treatment
        
                  -  Current or prior use of immunosuppressive medication within 14 days before the first
                     dose of their assigned IP; the following are exceptions to this criterion:
        
                       -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g.,
                          intra-articular injection)
        
                       -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
                          prednisone or its equivalent
        
                       -  Steroids as pre-medication for hypersensitivity reactions (e.g., CT scan
                          pre-medication)
        
                  -  Major surgical procedure (as defined by the investigator) within 28 days prior to the
                     first dose of IP; Note: local surgery of isolated lesions for palliative intent is
                     acceptable
        
                  -  History of allogeneic organ transplantation
        
                  -  Active or prior documented autoimmune or inflammatory disorders (including
                     inflammatory bowel disease, diverticulitis [with the exception of diverticulosis];
                     sarcoidosis syndrome, or other serious gastrointestinal [GI] chronic conditions
                     associated with diarrhea; systemic lupus erythematosus; Wegener syndrome
                     [granulomatosis with polyangiitis]; myasthenia gravis; Graves disease; rheumatoid
                     arthritis; hypophysitis; uveitis, sarcoidosis syndrome, etc.) within the past 3 years
                     prior to the start of treatment; the following are exceptions to this criterion:
        
                       -  Patients with vitiligo or alopecia
        
                       -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                          hormone replacement or psoriasis not requiring systemic treatment
        
                       -  Any chronic skin condition that does not require systemic therapy
        
                       -  Patients without active disease in the last 5 years may be included but only
                          after consultation with the study physician
        
                       -  Patients with celiac disease controlled by diet alone
        
                  -  History of another primary malignancy except for
        
                       -  Malignancy treated with curative intent and with no known active disease >= 5
                          years before the first dose of study drug and of low potential risk for
                          recurrence
        
                       -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                          of disease
        
                       -  Adequately treated carcinoma in situ without evidence of disease (e.g., cervical
                          cancer in situ)
        
                  -  Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3
                     electrocardiograms (ECGs) using Fridericia's correction
        
                  -  History of active primary immunodeficiency
        
                  -  Known history of previous clinical diagnosis of tuberculosis
        
                  -  Active infection including hepatitis B (known positive hepatitis B virus [HBV] surface
                     antigen [HBsAg]) result or, hepatitis C; patients with a past or resolved HBV
                     infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence
                     of HBsAg) are eligible; patients positive for hepatitis C (HCV) antibody are eligible
                     only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
        
                  -  Receipt of live, attenuated vaccine within 30 days prior to the first dose of
                     investigational treatment; Note: patients, if enrolled, should not receive live
                     vaccine during the study and up to 30 days after the last dose of investigational
                     treatment
        
                  -  Any condition that, in the opinion of the investigator, would interfere with
                     evaluation of the investigational treatment or interpretation of patient safety or
                     study results
        
                  -  Cohort 1 (NSCLC cohort)
        
                       -  In regards to administration of prior anti-PD-1 or anti PD-L1 antibodies, a
                          patients:
        
                            -  Must not have experienced a toxicity that led to permanent discontinuation
                               of prior immunotherapy
              
        Maximum Eligible Age:N/A
        Minimum Eligible Age:18 Years
        Eligible Gender:All
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Overall response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
        Time Frame:Up to 2 years
        Safety Issue:
        Description:The proportion of patients with response (complete response or partial response according to RECIST) will be compared for each pair-wise comparison of radiotherapy (RT)-containing therapy and control using chi- squared tests. The difference between the proportions responding will be presented with a 90% confidence interval. For colorectal cancer, response rates within each two-stage design will be calculated and presented with 90% confidence intervals estimated using the method of Atkinson and Brown, which allows for the two-stage design.

        Secondary Outcome Measures

        Measure:Progression-free survival (PFS)
        Time Frame:From date of randomization until objective disease progression or death, whichever occurs first, assessed up to 2 years
        Safety Issue:
        Description:Distributions will be summarized using the Kaplan-Meier method. Median times for each therapy arm will be accompanied by 90% confidence intervals based on log(-log(endpoint)) methodology. For cohort 1, the pairwise comparisons between the durvalumab/tremelimumab alone and durvalumab/tremelimumab with RT arms will be conducted using log-rank tests.
        Measure:Overall survival (OS)
        Time Frame:From time of randomization to death from any cause, assessed up to 2 years
        Safety Issue:
        Description:Distributions will be summarized using the Kaplan-Meier method. Median times for each therapy arm will be accompanied by 90% confidence intervals based on log(-log(endpoint)) methodology. For cohort 1, the pairwise comparisons between the durvalumab/tremelimumab alone and durvalumab/tremelimumab with RT arms will be conducted using log-rank tests.
        Measure:Objective response per immune-related response criteria
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Will be presented with 90% exact binomial confidence intervals. For cohort sizes of 30 (cohort 2) and 40 patients (cohort 1), the confidence intervals will be no wider than 0.32 and 0.28, respectively. For cohort 1, the pairwise comparisons of irORR between RT and the control arm will be conducted using chi-squared tests.
        Measure:Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Safety data will be summarized for each treatment arm within each cohort. The proportions of subjects with grade-3 or higher adverse events will be presented with exact binomial confidence intervals.
        Measure:Local control rate and abscopal response rates
        Time Frame:Up to 2 years
        Safety Issue:
        Description:The proportions of patients with local control within the irradiated field will be reported within each RT treatment arm and presented with 90% exact binomial confidence intervals. Similar presentations will be used for abscopal response rates. For cohort sizes of 30 (cohort 2) and 40 patients (cohort 1), the confidence intervals will be no wider than 0.32 and 0.28, respectively.
        Measure:Prognostic effect of PD-L1 expression
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Clinical response will be compared according to PD-L1 expression using Fisher's exact tests.
        Measure:Prognostic effect of T-cell infiltration
        Time Frame:Up to 2 years
        Safety Issue:
        Description:Clinical response will be compared according to infiltration using Fisher's exact tests.

        Details

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

        Last Updated

        March 2, 2018