Neoadjuvant Immune Checkpoint Blockade in Resectable Malignant Pleural Mesothelioma

December 19, 2023 updated by: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
The proposed study will evaluate the safety and feasibility of neoadjuvant nivolumab +/- ipilimumab in resectable MPM. In addition, maintenance nivolumab will be administered for 1 year following completion of standard bi-/tri-modality therapy.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

For Arm A 15 patients with resectable MPM will be enrolled and receive preoperative nivolumab, 240mg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).

Subsequent to full accrual to Arm A, 15 patients with resectable MPM will be enrolled and receive preoperative nivolumab, 3mg/kg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) + ipilimumab 1mg/kg IV on Day -42 prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).

Study Type

Interventional

Enrollment (Estimated)

30

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Recruiting
        • Johns Hopkins University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Patrick Forde, MD
      • Baltimore, Maryland, United States, 21201
        • Recruiting
        • Greenebaum Comprehensive Cancer Center University of Maryland School of Medicine
        • Contact:
        • Principal Investigator:
          • Katherine Scilla, MD
        • Sub-Investigator:
          • Ranee Mehra, MD
        • Sub-Investigator:
          • Katherine E Arensmeyer, MD
    • Texas
      • Houston, Texas, United States, 77030
        • Recruiting
        • University of Texas M.D. Anderson Cancer Center
        • Contact:
        • Principal Investigator:
          • Boris Sepesi, MD
        • Sub-Investigator:
          • Anne Tsao, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Men and women ≥ 18 years old
  • Primary tumor amenable to safe research biopsy. A tumor biopsy is required for study entry.

  • Histology proven epithelial or biphasic MPM

    • Diagnostic core biopsy specimens must be reviewed by faculty pathologist at SKCC, MDACC, or UMGCCC.
    • Either a formalin fixed paraffin block that has been confirmed by a pathologist to contain tumor or a minimum of twenty 5-micron tissue sections (slides) of tumor biopsy sample must be available for biomarker evaluation (study pathologist must review for adequacy of sampling). This can be obtained from archived tissues if adequate, or from a new biopsy as needed.
  • Stage I-III and deemed to be potentially surgically resectable as assessed by faculty surgeon at SKCC, MDACC, or UMGCCC
  • ECOG performance status 0-1

  • Adequate organ function as follows:

    • Leukocytes ≥ 2,000/mm3
    • Absolute neutrophil count (ANC) ≥ 1000/mm3
    • Platelet count ≥ 100,000/mm3
    • Hemoglobin ≥ 9 g/Dl
    • Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

  • Total Bilirubin ≤ 1.5 x institutional ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
  • AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 3 times the institutional upper limit of normal

  • Subjects must have adequate lung function to permit surgical resection determined by pre-enrollment pulmonary function tests to include DLCO

    • The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for up to 23 weeks after the last dose of nivolumab. 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. Sexually active fertile men must use effective barrier birth control if their partners are WOCBP for up to 31 weeks after the last dose of nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration. Women must not be breastfeeding.
    • Patient understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form. Voluntary signed and dated IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Subjects must be competent to report AEs, understand the drug dosing schedule and use of medications to control AEs.

Exclusion Criteria:

  • Stage I-III disease but deemed to be unresectable, a poor surgical candidate, or unfit for study therapy as assessed by study investigators
  • Pure sarcomatoid histology
  • Subjects are excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
  • Subjects are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen.
  • Administration of chemotherapy or any other cancer therapy in the pre-operative period.
  • Subjects with active concurrent malignancies are excluded i.e. cancers other than MPM (except non-melanoma skin cancers, cervical dysplasia, and in situ cancers of bladder, stomach, breast, colon and cervix).
  • Subjects with a history of symptomatic interstitial lung disease.
  • Active systemic infection requiring therapy, as well as positive tests for hepatitis B surface antigen or hepatitis C antibody.
  • Known positive history or positive test for human immunodeficiency virus or Acquired Immunodeficiency Syndrome (AIDS).
  • History of allergy to study drug components.
  • Women who are pregnant or nursing.
  • Men with female partners (WOCBP) that are unwilling to use contraception
  • Prior therapy with an anti-PD1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody (or any other antibody targeting T-cell co-regulatory pathways).
  • History of any other condition that may require the initiation of anti-tumor necrosis factor alpha (TNFα) therapies or other immunosuppressant medications during the study
  • Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
  • Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm A Nivolumab Only
Receive preoperative nivolumab, 240mg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).
Drug: Nivolumab Injection
Receive preoperative nivolumab, 240mg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).
Other Names:
  • Optivo
Experimental: Arm B Nivolumab + Ipilimumab
Receive preoperative nivolumab, 3mg/kg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) + ipilimumab 1mg/kg IV on Day -42 prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).
Drug: Nivolumab Injection
Receive preoperative nivolumab, 240mg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).
Other Names:
  • Optivo
Drug: Ipilimumab Injection
Receive preoperative nivolumab, 3mg/kg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) + ipilimumab 1mg/kg IV on Day -42 prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).
Other Names:
  • Yervoy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety Profile of neoadjuvant nivolumab +/- ipilimumab in patients with resectable malignant pleural mesothelioma (MPM) with grade III/IV adverse events defined by CTCAE v5.0
Time Frame: up to 5 years
Number of participants with grade III/IV adverse events defined by CTCAE v5.0, occurring within 100 days of last study drug administration or 30 days post-surgery (whichever is longer).
up to 5 years
Feasibility of neoadjuvant nivolumab +/- ipilimumab in patients with resectable MPM who complete of neoadjuvant treatment and proceed to surgery
Time Frame: up to 5 years
Feasibility as measured by the number of participants who complete of neoadjuvant treatment with nivolumab +/- ipilimumab and proceed to surgery without extended treatment-related delay (>24 days from preplanned surgery date).
up to 5 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pathological Response to neoadjuvant nivolumab +/- ipilimumab in resected tumor and lymph nodes in patients with resectable MPM defined as ≤10% residual viable tumor cells and pathologic complete response
Time Frame: 5 years
Number of participants with pathologic response, defined as ≤10% residual viable tumor cells in the resection specimen, and pathologic complete response (no residual viable tumor cells in the resection specimen).
5 years
Radiographic Response to neoadjuvant nivolumab +/- ipilimumab utilizing RECIST 1.1
Time Frame: 5 years
Number of participants with radiographic response as determined utilizing RECIST 1.1, modified RECIST for pleural tumors, and change in FDG avidity on PET/CT pre- and post-treatment.
5 years
Toxicity as assessed by number of participants experienced grade III/IV adverse events as defined by CTCAE v5.0 within 100 days of last study drug administration
Time Frame: up to 100 days post-intervention
Toxicity as assessed by number of participants experienced grade III/IV adverse events as defined by CTCAE v5.0 within 100 days of last study drug administration
up to 100 days post-intervention

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Bristol-Myers Squibb

Investigators

  • Principal Investigator: Patrick Forde, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 2, 2019

Primary Completion (Estimated)

June 1, 2025

Study Completion (Estimated)

June 1, 2026

Study Registration Dates

First Submitted

April 15, 2019

First Submitted That Met QC Criteria

April 15, 2019

First Posted (Actual)

April 17, 2019

Study Record Updates

Last Update Posted (Actual)

December 26, 2023

Last Update Submitted That Met QC Criteria

December 19, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • J1932
  • IRB00203283 (Other Identifier: JHM IRB)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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