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A Study of NIVO Plus IPI and Guadecitabine or NIVO Plus IPI in Melanoma and NSCLC Resistant to Anti-PD1/PDL1 (NIBIT-ML1)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04250246
Recruitment Status : Not yet recruiting
First Posted : January 31, 2020
Last Update Posted : January 31, 2020
Sponsor:
Collaborators:
Astex Pharmaceuticals, Inc.
Bristol-Myers Squibb
Information provided by (Responsible Party):
Italian Network for Tumor Biotherapy Foundation

Tracking Information
First Submitted Date  ICMJE January 23, 2020
First Posted Date  ICMJE January 31, 2020
Last Update Posted Date January 31, 2020
Estimated Study Start Date  ICMJE March 2020
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2020)
Immune-related Objective Response Rate (iORR) [ Time Frame: 24 weeks ]
Immune-related Objective Response Rate (iORR) is the proportion of treated subjects with an iBOR of confirmed iCR or confirmed iPR.
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2020)
  • Safety of guadecitabine in combination with ipilimumab and nivolumab [ Time Frame: 2 years ]
    Reporting of safety, extent of exposure, concomitant medications and discontinuation of study therapy will be based on all treated subjects; for on-study laboratory test results, all treated subjects with at least one on-study laboratory measurement available will be included in the analysis. The reporting period for safety data will be from the date of first dose received on this study to 100 days after the last dose is received. Serious adverse events are reported from the time of consent forward for all subjects. All subjects who received at least one dose of study treatment will be evaluated for safety parameters
  • Obiective Response Rate (ORR) [ Time Frame: 24 weeks ]
    Objective Response Rate (ORR) is the proportion of treated subjects with a BOR of CR or PR per RECIST 1.1.
  • Disease Control Rate (DCR) [ Time Frame: 24 weeks ]
    Disease Control Rate (DCR) is the proportion of treated subjects with a BOR of confirmed CR, confirmed PR or SD, based on RECIST 1.1 and iRECIST.
  • Duration of response (DoR) [ Time Frame: 2 years ]
    Duration of Response (DoR) for the subjects whose BOR is CR or PR will be defined as the time between the date of response of confirmed CR or confirmed PR (whichever occurs first) and the date of PD or death (whichever occurs first), based on RECIST 1.1 and iRECIST.
  • Time to response (TTR) [ Time Frame: 24 weeks ]
    Time to Response (TTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of PR or CR (whichever status comes first, and provided it is subsequently confirmed), , based on RECIST 1.1 and iRECIST.
  • Progression Free Survival (PFS) [ Time Frame: 2 years ]
    Progression free survival (PFS) per RECIST 1.1 and iRECISTwill be defined as the time between the date of randomization and the date of progression and or confirmed PD (according to RECIST 1.1 and iRECIST) or death, whichever occurs first.
  • Overall Survival (OS) [ Time Frame: 2 years ]
    Overall Survival (OS) is defined as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive. Any efforts will be made to know the date of death.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of NIVO Plus IPI and Guadecitabine or NIVO Plus IPI in Melanoma and NSCLC Resistant to Anti-PD1/PDL1
Official Title  ICMJE A Randomized, run-in, Multi-center, Phase II Study of Nivolumab Combined With Ipilimumab and Guadecitabine or Nivolumab Combined With Ipilimumab in Melanoma and NSCLC Patients Resistant to Anti-PD-1/PD-L1 (NIBIT-ML1)
Brief Summary This is a run-in, randomized, non-comparative, phase II study designed according to a two stages optimal design by Simon. This phase II design will be preceded by a safety evaluation after the first cohort of 6 patients to preserve a high-grade of overlapping and/or unexpected toxicity rate. The study will assess the immune-objective response rate (iORR) (assessed using iRECIST criteria) of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in Melanoma and non-small cell lung cancer (NSCLC) patients resistant to anti-PD-1/PD-L1 therapy. Immune biologic correlates to treatment will be assessed as exploratory endpoints.
Detailed Description Epigenetic alterations play a pivotal role in cancer development and progression. Pharmacologic reversion of such alterations is feasible, second generation "epigenetic drugs" are in development and have demonstrated to possess significant immunomodulatory properties. This knowledge, together with the availability of new and highly effective immuno-therapeutic agents including immune check-point(s) blocking monoclonal antibodies, allows the investigators to plan for highly innovative proof-of-principle combination studies that will likely open the path to more effective anti-cancer therapies. Targeting immune check-point(s) with immunomodulatory monoclonal-antibodies is a novel and rapidly evolving strategy to treat cancer, that is rapidly spreading to different tumor histologies. The prototype approach of this therapeutic modality relies on the inhibition of negative signals delivered by CTLA-4 expressed on T lymphocytes. CTLA-4 blockade has profoundly changed the therapeutic landscape of melanoma, significantly improving the survival of patients; however, objective clinical responses are limited, and only a minority of patients achieves long-term disease control. Therefore, several combination approaches are being explored to improve the efficacy of CTLA-4 blockade. The anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have significantly increased the survival of melanoma and NSCLC patients. Despite this unprecedented efficacy, a significant proportion of melanoma and NSCLC patients fails to respond (primary resistance) or develops secondary resistance to anti-PD-1 treatment over time. Therefore, identifying new mechanism(s) underlying treatment failure(s), and designing novel combination/sequencing therapeutic approaches to overcome primary/secondary resistance is mandatory to improve the overall efficacy of anti-PD-1 therapy. The investigators have first demonstrated that epigenetic immune-modeling of cancer cells represents a key hallmark of cancer, as it impairs functional host's immune recognition of malignant cells; on the other hand, the investigators have shown the potential of epigenetic drugs, including DNA hypomethylating agents (DHA), to sensitize tumor cells to emerging immunotherapies. Based on these pre-clinical in vitro and in vivo findings, the investigators have most recently promoted the clinical translation of the immunomodulatory potential of epigenetic drugs through highly-innovative, hypothesis-driven, clinical trials. Along this line, the ongoing, exploratory, Investigator Initiated Trial (IIT) phase Ib NIBIT-M4 study, has evaluated safety and immunobiologic activities of the epigenetic priming with the next generation DHA guadecitabine followed by CTLA-4 blockade in MM patients (NCT02608437). The results of NIBIT-M4 study support the notion that DHA represent ideal "partner drugs" to improve the therapeutic efficacy of immune-checkpoint blockade, including the foreseeable role in reverting resistance to treatment. The NIBIT-ML1 study will assess the therapeutic efficacy of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in metastatic melanoma and NSCLC patient with primary resistance to anti-PD-1/PD-L1 therapy. Exploratory translational objectives will extensively investigate, on neoplastic cells, tumor microenveroinment and peripheral blood, immune-biologic correlates to treatment.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized, non-comparative, phase II study designed according to a two stages optimal design by Simon
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Melanoma
  • Non Small Cell Lung Cancer
Intervention  ICMJE
  • Drug: Ipilimumab plus nivolumab plus guadecitabine

    Cohort A Melanoma ARM A Guadecitabine: 30-45 mg/m2 s.c./day 1-5 q21 x 4 cycles and from W13 q28 x 6 cycles Ipilimumab: 3 mg/Kg i.v. plus nivolumab 1 mg/Kg i.v. on W1, 4, 7 and 10 and from W14 nivolumab 480 mg i.v. q4 wks for 2 years

    Cohort B NSCLC ARM A Guadecitabine: 30-45 mg/m2 s.c./day 1-5 q21 x 4 cycles and from W13 q28 x 6 cycles Ipilimumab: 1 mg/Kg i.v.q 6wks plus nivolumab 3 mg/Kg i.v. q2 wks until W13, then ipilimumab: 1 mg/Kg i.v. q 6wks plus nivolumab 480mg i.v. q4wks for 2 years

    Other Names:
    • ipilimumab (Yervoy)
    • nivolumab (Opdivo)
    • guadecitabine (SGI-110)
  • Drug: Ipilimumab plus nivolumab

    Cohort A Melanoma ARM B Ipilimumab: 3 mg/Kg i.v. plus nivolumab 1 mg/Kg i.v. on W1, 4, 7 and 10 and from W14 nivolumab 480 mg i.v. q4 wks for 2 years

    Cohort B NSCLC ARM B Ipilimumab: 1 mg/Kg i.v. q 6wks plus nivolumab 3 mg/Kg i.v. q2 wks until W13, then ipilimumab: 1 mg/Kg i.v. q6 wks plus nivolumab 480mg i.v. q4wks for 2 years.

    Other Names:
    • ipilimumab (Yervoy)
    • nivolumab (Opdivo)
Study Arms  ICMJE
  • Experimental: Ipilimuamb plus nivoluamb plus guadecitabine
    ipilimumab plus nivolumab combined with guadecitabine
    Intervention: Drug: Ipilimumab plus nivolumab plus guadecitabine
  • Active Comparator: Ipilimumab plus nivolumab
    Ipilimumab plus nivolumab
    Intervention: Drug: Ipilimumab plus nivolumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 29, 2020)
184
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2025
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Target Population Melanoma cohort A

    1. Histologic diagnosis of malignant melanoma
    2. Unresectable Stage III/Stage IV melanoma patients with resistance to anti-PD-1/PD-L1 and measurable lesions by CT or MRI per iRECIST/RECIST criteria that can be amenable to biopsy
    3. Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PD-L1 and its combinations; if BRAF mutant one line of targeted therapy is allowed prior to anti-PD-1/PD-L1therapy.
  2. Target Population NSCLC cohort B

    1. Histologic or cytologic diagnosis of NSCLC lackingEGFR-sensitizing mutation and/or ALK/ROS1 translocation.
    2. Stage IV NSCLC patients with primary resistance to anti-PD-1/PD-L1 and measurable lesions by CT or MRI per iRECIST/RECIST criteria that can be amenable to biopsy.
    3. Only one line of immunotherapy for advanced (unresectable Stage III or Stage IV) disease with anti-PD-1/PD-L1 or its combinations; one line of chemotherapy is allowed prior to anti-PD-1/PDL-1 therapy.
  3. confirmed PD
  4. 4 weeks or greater since last treatment and
  5. Must have recovered from any acute toxicity associated with prior therapy
  6. Life expectancy greater than 16 weeks
  7. Subjects with adequate organ function defined as:

    1. WBC ≥3500/uL
    2. ANC ≥2000/uL
    3. Platelets ≥ 100 x 103/uL
    4. Hemoglobin ≥ 9 g/dL
    5. Creatinine < or <= 2.5 x ULN
    6. AST

      • < or <= 2.5 x ULN for patients without liver metastasis
      • < or <= 5 x ULN for patients with liver metastasis
    7. Bilirubin

      • < or <= 3 x ULN for patients with liver metastasis
      • <3.0 mg/mL for patients with Gilbert's Syndrome
      • 1.5 x ULN for patients without liver metastasis
  8. Negative screening tests for HIV, HepB, and HepC. If positive results are not indicative of true active or chronic infection, the patient can enter the study after discussion and agreement between the Investigator and the Medical Monitor.
  9. Women of child-bearing potential must not be pregnant or breastfeeding, must have a negative pregnancy test at Screening and all men must be practicing two medically acceptable methods of birth control. Men should not father a child while receiving treatment with guadecitabine+ ipilimumab, and for 2 months following completion of treatment. Men with female partners of childbearing potential should use effective contraception during this time.

Exclusion Criteria:

  1. Sex and Reproductive Status

    1. Women who are pregnant or breastfeeding;
    2. WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 23 weeks after the study;
    3. Women with a positive pregnancy test on enrollment or prior to investigational product administration;
    4. Sexually active fertile men not using effective birth control if their partners are WOCBP
  2. Target Disease Exceptions

    1. Any malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix
    2. Primary ocular melanoma.
  3. Medical History and Concurrent Diseases

    1. Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery);
    2. Leptominingeal involvement by disease;
    3. Autoimmune disease: Patients with a documented history of Inflammatory Bowel Disease, including ulcerative colitis and Crohn's disease are excluded from this study as are patients with a documented history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis] and autoimmune hepatitis. Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome) are also excluded from this study;
    4. Any underlying medical condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
  4. Prohibited Treatments and/or Therapies

    1. Concomitant therapy with any anti-cancer agent; immunosuppressive agents; any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or radiotherapy (except palliative surgery and/or radiotherapy to treat a non-target symptomatic lesion or to the brain after Sponsor approval); other investigational anti-cancer therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses);
    2. Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
    3. Prior treatment with anti-CTLA-4, except in adjuvant setting Other Exclusion Criteria
    1. Prisoners or subjects who are involuntarily incarcerated;
    2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and to ensure that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Anna Maria Di Giacomo, MD +390577586338 a.m.digiacomo@ao-siena.toscana.it
Contact: Michele Maio, MD PhD +390577586335 mmaiocro@gmail.com
Listed Location Countries  ICMJE Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04250246
Other Study ID Numbers  ICMJE NIBIT-ML1
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Italian Network for Tumor Biotherapy Foundation
Study Sponsor  ICMJE Italian Network for Tumor Biotherapy Foundation
Collaborators  ICMJE
  • Astex Pharmaceuticals, Inc.
  • Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Anna Maria Di Giacomo, MD Center for Immuno-Oncology, University Hospital of Siena
PRS Account Italian Network for Tumor Biotherapy Foundation
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP