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Neoadjuvant Immune Checkpoint Blockade in Resectable Malignant Pleural Mesothelioma

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ClinicalTrials.gov Identifier: NCT03918252
Recruitment Status : Recruiting
First Posted : April 17, 2019
Last Update Posted : October 18, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Mesothelioma Drug: Nivolumab Injection Drug: Ipilimumab Injection Phase 1 Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant Immune Checkpoint Blockade in Resectable Malignant Pleural Mesothelioma
Actual Study Start Date : October 2, 2019
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Mesothelioma

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 Name: 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 Name: 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 Name: Yervoy




Primary Outcome Measures :
  1. 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).

  2. 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).


Secondary Outcome Measures :
  1. 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).

  2. 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.

  3. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03918252


Contacts
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Contact: Patrick Forde, MD 4109558893 pforde1@jhmi.edu
Contact: Heather Schneider, BS 4105020984 hschne12@jhmi.edu

Locations
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United States, Maryland
Greenebaum Comprehensive Cancer Center University of Maryland School of Medicine Not yet recruiting
Baltimore, Maryland, United States, 21201
Contact: Christian Rolfo, MD    410-328-7224    christian.rolfo@umm.edu   
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Patrick Forde, MD    410-955-8893    pforde1@jhmi.edu   
Contact: Heather Schneider, BS    4105020984    hschne12@jhmi.edu   
United States, Texas
University of Texas M.D. Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Boris Sepesi, MD    713-563-0135    BSepesi@mdanderson.org   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
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Principal Investigator: Patrick Forde, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications:
Noone AM, Howlader N, Krapcho M, et al. SEER cancer statistics review, 1975-2015, National Cancer institute, Bethesda, MD, 2018.
Quispel-Janssen J, Zago G, Schouten R, et al. OA13.01 A phase II study of nivolumab in malignant pleural mesothelioma (NivoMes): With translational research (TR) biopsies. J Thorac Oncol. 2017;12(1):s293.
Baas P, Disselhorst MJ, Harms E, et al. PL02.04: Ipilimumab and nivolumab in the treatment of malignant pleural mesothelioma: Final results of a phase II study (initiate). 14th International Conference of the International Mesothelioma Interest Group. 2018.
Scherpereel A, Mazieres J, Greillier L, et al. Second- or third-line nivolumab (nivo) versus nivo plus ipilimumab (ipi) in malignant pleural mesothelioma (MPM) patients: Results of the IFCT-1501 MAPS2 randomized phase II trial. JCO. 2017;35(18):LBA8507.
Scagliotti G, Gaafar R, Nowak A, et al. PL02.09 nintedanib + pemetrexed/cisplatin in patients with unresectable MPM: Phase III results from the lume-meso trial. IASLC 19th World Conference on Lung Cancer.
Desai A, Karrison T, Rose B, et al. OA08.03 phase II trial of pembrolizumab (NCT02399371) in previously treated malignant mesothelioma: Final analysis. J Thorac Oncol. 2018;13(10):S339.
Nakano T, Okada M, Kijima T, et al. OA08.01 long-term efficacy and safety of nivolumab in second- or third-line japanese malignant pleural mesothelioma patients (phase II: MERIT study). J Thorac Oncol. 2018;13(10):S338.
Nowak AK, Sei Kok P, Joost Lesterhuis W, et al. OA08.02 DREAM - A phase 2 trial of durvalumab with first line chemotherapy in mesothelioma: Final result. J Thorac Oncol. 2018;13(10):S339.
Rozeman EA, Blank CU, Van Akkooi A,Christopher Jonathan, et al. Neoadjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage III melanoma: Updated data from the OpACIN trial and first immunological analyses. JCO. 2017;35(15):9586.
Schmid P, Park YH, Muñoz-Couselo E, et al. Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173. JCO. 2017;35(15):556.
Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2. JCO. 2017;35(15):506.
Directive 2001/20/EC of the european parliament and of the council of 4 april 2001. Official Journal of the European Communities. 2001;L(121):35,36,37,38,39,40,41,42,43,44.
Powderly JD, Koeppen H, Hodi FS, et al. Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. JCO. 2013;31(15):3001.

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03918252     History of Changes
Other Study ID Numbers: J1932
IRB00203283 ( Other Identifier: JHM IRB )
First Posted: April 17, 2019    Key Record Dates
Last Update Posted: October 18, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
malignant
resectable
Additional relevant MeSH terms:
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Mesothelioma
Adenoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Mesothelial
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents