Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Cancers After Progression on PD-1 or PD-L1 Targeted Antibodies

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT04902040
Collaborator
(none)
12
1
2
49.6
0.2

Study Details

Study Description

Brief Summary

This phase Ib/II trial studies the side effects and best dose of plinabulin in combination with radiation therapy and immunotherapy in patients with select cancers that have spread to other places in the body (advanced) after progression on PD-1 or PD-L1 targeted antibodies. Plinabulin blocks tumor growth by targeting both new and existing blood vessels going to the tumor as well as killing tumor cells. Immunotherapy may induce changes in body's immune system and 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 plinabulin in combination with radiation therapy and immunotherapy may work better in treating advanced cancers.

Condition or Disease Intervention/Treatment Phase
  • Biological: Atezolizumab
  • Drug: Avelumab
  • Biological: Durvalumab
  • Biological: Nivolumab
  • Biological: Pembrolizumab
  • Drug: Plinabulin
  • Radiation: Radiation Therapy
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. To assess the safety and tolerability of plinabulin when administered in combination with radiation/immunotherapy regimen in subjects with select advanced solid malignancies after progression on anti-PD-1/PD-L1 monoclonal antibody (mAb).

  2. To assess the objective tumor response rate (complete response + partial response).

SECONDARY OBJECTIVES:
  1. To assess disease control rate (complete response, partial response + stable disease).

  2. To determine progression-free survival (PFS). III. To assess overall survival.

EXPLORATORY OBJECTIVES:
  1. To analyze the gene mutation density within each sample. II. To assess T-cell receptor (TCR) sequencing in tumor tissue and peripheral blood, pre- and post- treatment.

  2. To perform imaging mass flow cytometry (CyTOF) and/or single cell ribonucleic acid sequencing (RNAseq) analysis on tumor tissue: Immune phenotyping, including dendritic cell (DC), T cells, tumor-associated macrophage (TAM)s, pre and post treatment.

  3. To conduct phenotyping analysis of immune cells from peripheral blood using multicolor flow cytometry.

  4. To evaluate dendritic cell activation from whole blood upon the treatment. VI. To explore general predictive and response biomarker measurements from the collected biomarkers.

OUTLINE: This is a phase Ib, dose-escalation study of plinabulin followed by a phase II study. Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients receive plinabulin intravenously (IV) over 30-60 minutes on days 1 and 4 of cycle 1, days 1 and 4 of cycle 2 (if receiving radiation therapy in cycle 2), and day 1 and or 15 (any day receiving immunotherapy) of subsequent cycles. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 months.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
12 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-label, Single-Center, Phase 1b/2 Study to Evaluate the Safety of Plinabulin in Combination With Radiation/Immunotherapy in Patients With Select Advanced Malignancies After Progression on PD-1 or PD-L1 Targeted Antibodies
Actual Study Start Date :
Apr 14, 2021
Anticipated Primary Completion Date :
Jun 1, 2025
Anticipated Study Completion Date :
Jun 1, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A (radiation therapy, plinabulin, immunotherapy)

Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients receive plinabulin IV over 30-60 minutes on days 1 and 4 of cycle 1, days 1 and 4 of cycle 2 (if receiving radiation therapy in cycle 2), and day 1 and or 15 (any day receiving immunotherapy) of subsequent cycles. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

Biological: Atezolizumab
Given IV
Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq
  • Drug: Avelumab
    Given IV
    Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C
  • Biological: Durvalumab
    Given IV
    Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736
  • Biological: Nivolumab
    Given IV
    Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
  • Biological: Pembrolizumab
    Given IV
    Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475
  • Drug: Plinabulin
    Given IV
    Other Names:
  • NPI-2358
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Active Comparator: Arm B (radiation therapy, immunotherapy)

    Patients undergo radiation therapy on days 1-3, 1-4, or 1-5 of cycle 1. Patients may undergo additional radiation in cycle 2 at the discretion of treating physician. Patients also receive immunotherapy consisting of either: avelumab IV over 1 hour on days 1 and 15; atezolizumab over 30-60 minutes on day 1; durvalumab IV over 1 hour on days 1 and 15; nivolumab IV over 30-60 min on days 1 and 15; or pembrolizumab IV over 30 min on day 1. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

    Biological: Atezolizumab
    Given IV
    Other Names:
  • MPDL 3280A
  • MPDL 328OA
  • MPDL-3280A
  • MPDL3280A
  • MPDL328OA
  • RG7446
  • RO5541267
  • Tecentriq
  • Drug: Avelumab
    Given IV
    Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C
  • Biological: Durvalumab
    Given IV
    Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736
  • Biological: Nivolumab
    Given IV
    Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo
  • Biological: Pembrolizumab
    Given IV
    Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Outcome Measures

    Primary Outcome Measures

    1. Incidence of adverse events (AEs) [Up to 30 days after last dose of plinabulin]

      AEs will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

    2. Objective tumor response rate (ORR) (complete response + partial response) [Up to 4 years]

      Radiologic evaluations will be performed at screening and every 9 weeks (± 1 week) for 27 weeks (during Q3W dosing) or every 8 weeks (± 1 week) for 24 weeks (during Q4W dosing), then every 12 weeks during treatment cycles in the Treatment Phase regardless of treatment cycles and follow up period. Categorization of response will be based on both immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) and modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

    Secondary Outcome Measures

    1. Disease control rate (complete response, partial response + stable disease) [Up to 4 years]

      Assessed according to irRECIST criteria.

    2. Progression-free survival [From the first study dose date to the date of first documentation of confirmed disease progression or death (whichever occurs first), assessed up to 4 years]

      Will be analyzed using Kaplan-Meier method or Cox regression.

    3. Overall survival [From the start date of the treatment period until date of death from any cause, assessed up to 4 years]

      Will be analyzed using Kaplan-Meier method or Cox regression.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Subjects must have one of seven histologically or cytologically confirmed malignant neoplasms (non-small cell lung cancer, small cell lung cancer, renal cell cancer, bladder cancer, Merkle cell cancer, microsatellite instability high (MSI-H) cancer (any histology), and melanoma) progressed on previous anti-PD-1/PD-L1 mAb treatment +/- chemotherapy or anti-CTLA4 requiring further treatment

    • At least one lesion is amenable to radiation

    • At least one additional non-contiguous lesion that has not been irradiated amenable to radiographic evaluation

    • Have measurable disease based on immune-related response criteria (immune-related Response Evaluation Criteria In Solid Tumors [RECIST])

    • Tissue must be newly obtained as a core needle biopsy (not fine-needle aspiration [FNA]) of the lesion being evaluated

    • Age >= 18 years

    • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

    • Subjects must be recovered from any prior major surgery. The major surgery must be performed at least 4 weeks prior to consent date

    • Platelets >= 100 x 10^9/L

    • Transfusions and growth factors are allowed

    • Hemoglobin >= 9 g/dL

    • Transfusions and growth factors are allowed

    • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

    • Transfusions and growth factors are allowed

    • White blood cell (WBC) >= 3 x 10^9/L

    • Transfusions and growth factors are allowed

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN) (=< 1.5 x ULN if alkaline phosphatase is > 2.5 x ULN) (In the expansion cohort, subjects with known liver involvement may have ALT =< 5 x ULN)

    • Alkaline phosphatase < 4 x ULN

    • Total bilirubin =< 1 x ULN (In the expansion cohort, subjects with Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of =< 3 x ULN)

    • Albumin >= 3 g/dL

    • Renal function defined as a calculated or measured glomerular filtration rate (GFR) >= 30 mL/min and Cockcroft-Gault equation

    • The patient has recovered to grade =< 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) from the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other targeted therapies, with the exception of alopecia. The exceptions for such effects are allowed lab values of =< grade 2 specified elsewhere in these inclusion criteria

    • Subjects must give informed consent according to the rules and regulations of the individual participating sites

    • Negative urine pregnancy test in women of child bearing potential within 7 days of first dose of treatment and subjects of child-bearing potential must agree to use effective contraception during and for 5 months following the last dose of atezolizumab or nivolumab, and for 4 months after the last dose of pembrolizumab, and for 3 months after last dose of durvalumab and avelumab, and for 3 months after your last dose of plinabulin. A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable or mechanical contraception; women who are single and women whose male sexual partners have been vasectomized or whose male sexual partners have received or are utilizing mechanical contraceptive devices

    Exclusion Criteria:
    • Evidence of complete or partial bowel obstruction

    • Subjects with primary central nervous system (CNS) tumor or CNS tumor involvement. However, subjects with metastatic CNS tumors may participate in this study if the patient is:

    • 4 weeks from prior therapy completion

    • Clinically stable with respect to the CNS tumor at the time of study entry

    • Not receiving steroid therapy in treating CNS tumor or CNS tumor involvement

    • Not receiving anti-convulsive medications (that were started for brain metastases)

    • Need of total parenteral nutrition

    • Allergic to any of anti-PD-1/PD-L1 monoclonal antibody (mAb) intended to receive

    • Prior exposure to plinabulin

    • Pregnancy or lactation

    • Radiation (except planned or ongoing palliative radiation to bone outside of the region of measurable disease) =< 3 weeks prior to study drug administration date

    • Chemotherapy, or immunotherapy or any other systemic anticancer therapy =< 3 weeks prior to study drug administration date except anti-PD-1/PD-L1 mAb mono or combination therapy

    • Diagnosis or recurrence of invasive cancer other than the present cancer within 3 years (except basal or squamous cell carcinoma of the skin that has been definitively treated)

    • Major surgery within four weeks before consent date

    • Unstable cardiovascular function or active cardiac disease:

    • Symptomatic ischemia (chest pain of cardiac origin),or

    • Uncontrolled clinically significant conduction abnormalities (e.g. ventricular tachycardia on antiarrhythmics are excluded; 1st degree AV block or asymptomatic Left anterior fascicular block (LAFB)/ right bundle branch block (RBBB) will not be excluded),or

    • Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3, or

    • Myocardial infarction (MI) within 3 months of consent date

    • Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to the first dose. Active infection with concurrent treatment is acceptable only if the patient is clinically stable

    • Subject is known to be positive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C

    • Significantly diseased (as determined by the PI or treating physician) or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea. Presence of ileus or other significant gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility

    • Treatment with an investigational anti-cancer study drug within 3 weeks prior to study drug administration date

    • Concurrent therapy with approved or investigational anticancer therapeutics

    • Medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

    • Men whose partner is a woman of child-bearing potential, (i.e. biologically able to conceive), and who is not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 5 months following the last dose of atezolizumab or nivolumab, for 4 months after the last dose of pembrolizumab, and for 3 months after last dose of durvalumab and avelumab, and for 3 months after your last dose of plinabulin. Women of child-bearing potential is defined as sexually mature women who are not surgically sterile or who have not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had menses any time in the preceding 12 consecutive months)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 M D Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center

    Investigators

    • Principal Investigator: Vivek Subbiah, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT04902040
    Other Study ID Numbers:
    • 2020-0296
    • NCI-2021-03489
    • 2020-0296
    First Posted:
    May 26, 2021
    Last Update Posted:
    Jul 1, 2022
    Last Verified:
    Jun 1, 2022

    Study Results

    No Results Posted as of Jul 1, 2022