Clinical Trials /

Anti-CTLA4-NF mAb (BMS986218), Nivolumab, and Stereotactic Body Radiation Therapy for the Treatment of Metastatic Solid Malignancies

NCT04785287

Description:

This phase I/II trial studies the side effects of anti-CTLA4-NF monoclonal antibody (mAb) (BMS986218), nivolumab, and stereotactic body radiation therapy in treating patients with solid malignancies that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as anti-CTLA4-NF mAb (BMS-986218) and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving -CTLA4-NF mAb (BMS986218), nivolumab, and stereotactic body radiation therapy may kill more tumor cells.

Related Conditions:
  • Adrenal Gland Neoplasm
  • Liver and Intrahepatic Bile Duct Carcinoma
  • Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anti-CTLA4-NF mAb (BMS986218), Nivolumab, and Stereotactic Body Radiation Therapy for the Treatment of Metastatic Solid Malignancies
  • Official Title: Phase I/II Trial of Anti-CTLA4-NF mAb (BMS-986218) in Combination With Nivolumab and Hypofractionated Stereotactic Radiation Therapy in Patients With Advanced Solid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2020-0479
  • SECONDARY ID: NCI-2021-01619
  • SECONDARY ID: 2020-0479
  • NCT ID: NCT04785287

Conditions

  • Advanced Lung Carcinoma
  • Advanced Malignant Solid Neoplasm
  • Malignant Adrenal Gland Neoplasm
  • Metastatic Liver Carcinoma
  • Metastatic Lung Carcinoma
  • Metastatic Malignant Solid Neoplasm
  • Stage III Liver Cancer
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Stage IV Liver Cancer
  • Stage IV Lung Cancer AJCC v8
  • Stage IVA Liver Cancer
  • Stage IVA Lung Cancer AJCC v8
  • Stage IVB Liver Cancer
  • Stage IVB Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
Anti-CTLA4 Monoclonal Antibody BMS-986218BMS 986218, BMS-986218, Monoclonal Antibody BMS-986218Arm I (BMS-986218, SBRT)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm II (BMS-986218, SBRT, nivolumab)

Purpose

This phase I/II trial studies the side effects of anti-CTLA4-NF monoclonal antibody (mAb) (BMS986218), nivolumab, and stereotactic body radiation therapy in treating patients with solid malignancies that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as anti-CTLA4-NF mAb (BMS-986218) and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving -CTLA4-NF mAb (BMS986218), nivolumab, and stereotactic body radiation therapy may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the safety profile of intravenous anti-CTLA4 monoclonal antibody BMS-986218
      (anti-CTLA4-NF mAb [BMS-986218]) alone or with nivolumab administered in combination with
      stereotactic body radiation therapy (SBRT) targeting 1-4 lesion(s) for patients with
      metastatic cancers.

      SECONDARY OBJECTIVES:

      I. To determine antitumor activity of anti-CTLA4-NF mAb (BMS-986218) therapy with SBRT
      treatment for 1-4 lesions in non-irradiate tumors (abscopal lesions; out of external beam
      radiation [XRT] field) as defined by Immune-Related Response Criteria (irRC).

      II. To determine antitumor activity of anti-CTLA4-NF mAb (BMS-986218) therapy with RadScopal
      treatment in the low dose treated lesion as defined by irRC.

      III. To evaluate treatment efficacy in different SBRT treatment sites (liver versus [vs.]
      adrenal, lung vs. adrenal).

      IV. To evaluate treatment efficacy by comparing anti-CTLA4-NF mAb (BMS-986218) alone with
      SBRT treatment vs. anti-CTLA4-NF mAb (BMS-986218) in combination with nivolumab and SBRT
      treatment.

      EXPLORATORY OBJECTIVES:

      I. To evaluate treatment efficacy by comparing anti-CTLA4-NF mAb (BMS-986218) alone or with
      SBRT treatment vs. ipilimumab alone or with SBRT treatment (previous trial).

      II. To evaluate the associations of tumor-associated and systemic immune biomarkers for
      therapy with clinical response outcomes and toxicity prediction.

      III. To evaluate whether skeletal mass, neutrophil, neutrophil to lymphocyte ratio, and tumor
      bulk are correlated with clinical outcomes and adverse events.

      IV. To evaluate whether tumor kinetics in combination with clinical correlates can help
      determine treatment response.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive anti-CTLA4 monoclonal antibody BMS-986218 intravenously (IV) over 30
      minutes on day 1. Treatment repeats every 28 days for 4 cycles in the absence of disease
      progression or unacceptable toxicity. Patients also undergo SBRT on days 36-39 (days 8-11 of
      cycle 2).

      ARM II: Patients receive anti-CTLA4 monoclonal antibody BMS-986218 and SBRT as in Arm 1.
      Beginning cycle 2, patients also receive nivolumab IV over 30 minutes starting on day 1.
      Cycles repeat every 28 days for up to 2 years in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 60 days and 6 and 12
      months after last cycle of anti-CTLA4 monoclonal antibody BMS-986218.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (BMS-986218, SBRT)ExperimentalPatients receive anti-CTLA4 monoclonal antibody BMS-986218 IV over 30 minutes on day 1. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo SBRT on days 36-39 (days 8-11 of cycle 2).
  • Anti-CTLA4 Monoclonal Antibody BMS-986218
Arm II (BMS-986218, SBRT, nivolumab)ExperimentalPatients receive anti-CTLA4 monoclonal antibody BMS-986218 and SBRT as in Arm 1. Beginning cycle 2, patients also receive nivolumab IV over 30 minutes starting on day 1. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Anti-CTLA4 Monoclonal Antibody BMS-986218
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histological confirmation of solid metastatic cancer with at least
             one metastatic or primary lesion in the adrenal, liver or lung/chest

          -  Patients who have completed prior systemic anti-cancer therapies, an interval of 5
             drug half-lives or 4-weeks whichever is shorter, is required, prior to enrollment on
             study. Note: patients with anaplastic thyroid carcinoma will be waived from this
             inclusion criteria given the rapid trajectory of their disease

          -  All patients must have at least one metastatic or primary lesion within the
             lung/chest, liver or adrenal located in an anatomical location amenable to SBRT
             treatment with 50 Gy in 4 fractions. Patients may not have more than 80% liver
             displaced with cancer

          -  Repeat radiation in fields previously radiated will be allowed at the discretion of
             the treating physician

          -  Age >= 18 years

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin)
             within 24 hours prior to the start of study treatment. Subjects of childbearing
             potential are those who have not been surgically sterilized or have not been in
             postmenopausal state. Females in postmenopausal state under the age of 55 years must
             have a serum follicle stimulating hormone, (FSH) level > 40 mIU/mL to confirm
             menopause

          -  Women must not be breastfeeding for the duration of the study and 105 days AFTER
             completion of study treatment for BMS-986218 monotherapy treatment, 155 days AFTER
             completion of combination therapy (BMS-986218 + nivolumab) or 5 months AFTER
             completion of nivolumab maintenance treatment

          -  WOCBP receiving monotherapy or combination therapy treatment with BMS-986218 must
             agree to follow instructions for method(s) of contraception or be surgically sterile,
             or abstain from heterosexual activity for the duration of the study and 105 days AFTER
             completion of study treatment for BMS-986218 monotherapy treatment, 155 days AFTER
             completion of combination therapy (BMS-986218 + nivolumab) or 5 months AFTER
             completion of nivolumab maintenance treatment. WOCBP who are continuously not
             heterosexually active are exempt from contraceptive requirements, but should still
             undergo pregnancy testing as described in this section. In the case of male
             participants, during the course of treatment and 165 days AFTER the end of BMS-986218
             monotherapy treatment or 215 days AFTER the end of combination therapy treatment
             (BMS-986218 + nivolumab) or 7 months AFTER completion of nivolumab maintenance
             treatment the participant should not father a child (condom use is mandatory, even if
             vasectomized) or donate sperm. Local laws and regulations may require use of
             alternative and/or additional contraception methods

          -  Male participants who are sexually active with WOCBP must agree to follow instructions
             for methods of contraception during monotherapy treatment with BMS-986218 plus 5
             half-lives (75 days) of BMS-986218 plus 90 days for a total of 165 days after the end
             of BMS-986218 monotherapy treatment or 215 days after the end of combination therapy
             treatment (BMS-986218 + nivolumab), or 7 months AFTER completion of nivolumab
             maintenance treatment. In addition, male participants must be willing to refrain from
             sperm donation during this time

          -  Investigators shall counsel WOCBP, and male participants who are sexually active with
             WOCBP, on the importance of pregnancy prevention and the implications of an unexpected
             pregnancy. Investigators shall advise on the use of highly effective methods of
             contraception that have a failure rate of < 1% when used consistently and correctly

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky > 60%)

          -  Patients must have normal organ and marrow function as defined below: (use of growth
             factors or blood transfusion to achieve these requirements is not allowed 2 weeks
             prior to study enrollment). The blood test for the following analytes will be
             performed at screening/baseline and at the first day of every BMS-986218 therapy cycle

          -  Total bilirubin =< 2.0 x upper limit of normal (ULN), except participants with
             Gilbert's syndrome who must have normal direct bilirubin

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
             2.5 X institutional upper limit of normal

          -  Whole blood cell (WBC) >= 2500/uL

          -  Absolute neutrophil count (ANC) >= 1000/uL

          -  Platelets >= 75K

          -  Hemoglobin >= 9 g/dL

          -  Creatinine =< 1.5 x ULN, or creatinine clearance (CrCl) >= 40 mL/min (measured using
             the Cockcroft-Gault formula)

          -  Patients must be willing and able to review, understand, and provide written consent
             before starting therapy

          -  Patients with brain metastasis will be included as long as they are free of neurologic
             symptoms related to metastatic brain lesions and do not require or receive steroid
             therapy or brain metastasis. We will allow patients with stable brain metastases (no
             radiographic progression for at least 4 weeks following radiation and/or surgery or 4
             weeks of observation), no longer taking steroids for at least 2 weeks prior to first
             dose of study treatment, and with no new neurological signs and symptoms (clinically
             and radiographically) for >= 4 weeks to enroll on the protocol

          -  Patients that have previously progressed on immunotherapy such as ipilimumab,
             anti-PD-I, anti-PDL-1 or talimogene laherparepvec (T-VEC) will be eligible, but
             progression on immunotherapy is not required

        Exclusion Criteria:

          -  Patients with active, known, or suspected with autoimmune disorders or those who are
             at risk for flare of auto-immunity or immune-related diseases

          -  Participants with well controlled asthma and/or mild allergic rhinitis (seasonal
             allergies) are eligible

          -  Participants with the following disease conditions are also eligible:

               -  Vitiligo.

               -  Type 1 diabetes mellitus.

               -  Residual hypothyroidism due to autoimmune condition only requiring hormone
                  replacement.

               -  Euthyroid participants with a history of Grave's disease (participants with
                  suspected autoimmune thyroid disorders must be negative for thyroglobulin and
                  thyroid peroxidase antibodies and thyroid stimulating immunoglobulin [Ig] prior
                  to the first dose of study treatment).

               -  Psoriasis not requiring systemic treatment, or conditions not expected to recur
                  in the absence of an external trigger are permitted to enroll

          -  Active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction,
             abdominal carcinomatosis or other known risk factors for bowel perforation

          -  Any underlying medical or psychiatric condition, which in the opinion of the
             Investigator, will make the administration of study drug hazardous or obscure the
             interpretation of adverse event (AE)s: e.g. a condition associated with frequent
             diarrhea or chronic skin conditions, recent surgery or colonic biopsy from which the
             patient has not recovered, or partial endocrine organ deficiencies

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, history of congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Known human immunodeficiency virus (HIV) positive status or with positive test for
             hepatitis B surface antigen. Patients with hepatitis C antibody (Ab) positive will be
             considered for enrollment only if quantitative polymerase chain reaction (PCR) is
             negative

          -  Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to
             one month prior to or after any dose of BMS-986218). The use of inactivated seasonal
             influenza vaccines (e.g., Fluzone), will be permitted on study without restriction

          -  Concomitant therapy with any of the following: IL-2, interferon or other non-study
             immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other
             investigational therapies; or chronic use of systemic corticosteroids while receiving
             BMS-986218 (as long as steroid replacement is greater than what is required for
             physiologic replacement, i.e. in hypothyroidism, adrenal insufficiency)

          -  History of or current immunodeficiency disease or prior treatment compromising immune
             function at the discretion of the treating physician

          -  Prior allogeneic stem cell transplantation or organ allograft

          -  Patients who were intolerant to previous immuno-oncology (IO) drugs with side effects
             (grade 4 or greater) that were unable to be resolved with treatment, should be
             excluded

          -  Patients that have previously received or progressed on any anti-CTLA4-NF drug

          -  Absolute lymphocyte count below 0.4 x 10^9/L
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:The incidence of clinical and laboratory adverse events will be reported and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be reported in frequency tables overall, by intensity, and by relationship. Laboratory values will be reported in shift tables and with summary statistics. Chi-squared or Fisher exact tests will be used to compare safety between two arms. Logistic regression may be used to evaluate the predictive potential of tumor-associated and systemic immune biomarkers for toxicity prediction, and whether skeletal mass, neutrophil, neutrophil to lymphocyte ratio, and tumor bulk are correlated with adverse events.

Secondary Outcome Measures

Measure:Tumor response
Time Frame:Up to 12 months
Safety Issue:
Description:Will be determined using the Immune Related Response Criteria calculated for each arm with 95% exact confidence intervals. Will evaluate for the % abscopal response, which is defined as the best response rate, summing both complete response (CR) and partial response (PR) patients. This will be a measurement of the non-irradiated lesions. The clinical benefit will be defined as CR+ PR + stable disease (minimum of 6 months from time of enrolment). For patients that have progressive disease at the first treatment study (before re-induction treatment with RadScopal radiation therapy), Immune Related Response Criteria response criteria will be also used to evaluate the responses outside the irradiated tumors. Chi-squared test or Fisher exact test will be used to compare the response rate between two arms and different stereotactic body radiation therapy treatment sites (liver versus [vs.] adrenal, lung vs adrenal).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

March 5, 2021