- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04250246
A Study of NIVO Plus IPI and Guadecitabine or NIVO Plus IPI in Melanoma and NSCLC Resistant to Anti-PD1/PDL1 (NIBIT-ML1)
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)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Study Type
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Anna Maria Di Giacomo, MD
- Phone Number: +390577586338
- Email: a.m.digiacomo@ao-siena.toscana.it
Study Contact Backup
- Name: Michele Maio, MD PhD
- Phone Number: +390577586335
- Email: mmaiocro@gmail.com
Study Locations
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Siena, Italy, 53100
- Center for Immuno-Oncology, University Hospital of Siena
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Contact:
- Anna Maria Di Giacomo, MD
- Phone Number: +390577586305
- Email: a.m.digiacomo@ao-siena.toscana.it
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Contact:
- Giovanni Amato, PhD
- Phone Number: +390577586326
- Email: dataman.immonco@gmail.com
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
Target Population Melanoma cohort A
- Histologic diagnosis of malignant melanoma
- 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
- 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.
Target Population NSCLC cohort B
- Histologic or cytologic diagnosis of NSCLC lackingEGFR-sensitizing mutation and/or ALK/ROS1 translocation.
- 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.
- 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.
- confirmed PD
- 4 weeks or greater since last treatment and
- Must have recovered from any acute toxicity associated with prior therapy
- Life expectancy greater than 16 weeks
Subjects with adequate organ function defined as:
- WBC ≥3500/uL
- ANC ≥2000/uL
- Platelets ≥ 100 x 103/uL
- Hemoglobin ≥ 9 g/dL
- Creatinine < or <= 2.5 x ULN
AST
- < or <= 2.5 x ULN for patients without liver metastasis
- < or <= 5 x ULN for patients with liver metastasis
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
- 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.
- 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:
Sex and Reproductive Status
- Women who are pregnant or breastfeeding;
- 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;
- Women with a positive pregnancy test on enrollment or prior to investigational product administration;
- Sexually active fertile men not using effective birth control if their partners are WOCBP
Target Disease Exceptions
- 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
- Primary ocular melanoma.
Medical History and Concurrent Diseases
- Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery);
- Leptominingeal involvement by disease;
- 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;
- 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.
Prohibited Treatments and/or Therapies
- 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);
- Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;
- Prior treatment with anti-CTLA-4, except in adjuvant setting Other Exclusion Criteria
- Prisoners or subjects who are involuntarily incarcerated;
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Ipilimuamb plus nivoluamb plus guadecitabine
ipilimumab plus nivolumab combined with guadecitabine
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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:
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Active Comparator: Ipilimumab plus nivolumab
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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:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Immune-related Objective Response Rate (iORR)
Time Frame: 24 weeks
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Immune-related Objective Response Rate (iORR) is the proportion of treated subjects with an iBOR of confirmed iCR or confirmed iPR.
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24 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Safety of guadecitabine in combination with ipilimumab and nivolumab
Time Frame: 2 years
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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
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2 years
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Obiective Response Rate (ORR)
Time Frame: 24 weeks
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Objective Response Rate (ORR) is the proportion of treated subjects with a BOR of CR or PR per RECIST 1.1.
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24 weeks
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Disease Control Rate (DCR)
Time Frame: 24 weeks
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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.
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24 weeks
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Duration of response (DoR)
Time Frame: 2 years
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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.
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2 years
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Time to response (TTR)
Time Frame: 24 weeks
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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.
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24 weeks
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Progression Free Survival (PFS)
Time Frame: 2 years
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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.
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2 years
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Overall Survival (OS)
Time Frame: 2 years
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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.
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2 years
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Collaborators and Investigators
Investigators
- Principal Investigator: Anna Maria Di Giacomo, MD, Center for Immuno-Oncology, University Hospital of Siena
Publications and helpful links
General Publications
- Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8.
- Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Sep 24;373(13):1270-1. doi: 10.1056/NEJMc1509660. No abstract available. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.
- Maio M, Di Giacomo AM, Robert C, Eggermont AM. Update on the role of ipilimumab in melanoma and first data on new combination therapies. Curr Opin Oncol. 2013 Mar;25(2):166-72. doi: 10.1097/CCO.0b013e32835dae4f.
- Maio M, Covre A, Fratta E, Di Giacomo AM, Taverna P, Natali PG, Coral S, Sigalotti L. Molecular Pathways: At the Crossroads of Cancer Epigenetics and Immunotherapy. Clin Cancer Res. 2015 Sep 15;21(18):4040-7. doi: 10.1158/1078-0432.CCR-14-2914.
- Sigalotti L, Fratta E, Coral S, Maio M. Epigenetic drugs as immunomodulators for combination therapies in solid tumors. Pharmacol Ther. 2014 Jun;142(3):339-50. doi: 10.1016/j.pharmthera.2013.12.015. Epub 2013 Dec 30.
- Di Giacomo AM, Covre A, Finotello F, Rieder D, Danielli R, Sigalotti L, Giannarelli D, Petitprez F, Lacroix L, Valente M, Cutaia O, Fazio C, Amato G, Lazzeri A, Monterisi S, Miracco C, Coral S, Anichini A, Bock C, Nemc A, Oganesian A, Lowder J, Azab M, Fridman WH, Sautes-Fridman C, Trajanoski Z, Maio M. Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial. Clin Cancer Res. 2019 Dec 15;25(24):7351-7362. doi: 10.1158/1078-0432.CCR-19-1335. Epub 2019 Sep 17.
- Covre A, Coral S, Di Giacomo AM, Taverna P, Azab M, Maio M. Epigenetics meets immune checkpoints. Semin Oncol. 2015 Jun;42(3):506-13. doi: 10.1053/j.seminoncol.2015.02.003. Epub 2015 Feb 14.
- Hodi FS, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Cowey CL, Lao CD, Schadendorf D, Wagstaff J, Dummer R, Ferrucci PF, Smylie M, Hill A, Hogg D, Marquez-Rodas I, Jiang J, Rizzo J, Larkin J, Wolchok JD. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Nov;19(11):1480-1492. doi: 10.1016/S1470-2045(18)30700-9. Epub 2018 Oct 22. Erratum In: Lancet Oncol. 2018 Dec;19(12):e668. Lancet Oncol. 2018 Nov;19(11):e581.
- Ready N, Hellmann MD, Awad MM, Otterson GA, Gutierrez M, Gainor JF, Borghaei H, Jolivet J, Horn L, Mates M, Brahmer J, Rabinowitz I, Reddy PS, Chesney J, Orcutt J, Spigel DR, Reck M, O'Byrne KJ, Paz-Ares L, Hu W, Zerba K, Li X, Lestini B, Geese WJ, Szustakowski JD, Green G, Chang H, Ramalingam SS. First-Line Nivolumab Plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer (CheckMate 568): Outcomes by Programmed Death Ligand 1 and Tumor Mutational Burden as Biomarkers. J Clin Oncol. 2019 Apr 20;37(12):992-1000. doi: 10.1200/JCO.18.01042. Epub 2019 Feb 20.
- Lebbe C, Meyer N, Mortier L, Marquez-Rodas I, Robert C, Rutkowski P, Menzies AM, Eigentler T, Ascierto PA, Smylie M, Schadendorf D, Ajaz M, Svane IM, Gonzalez R, Rollin L, Lord-Bessen J, Saci A, Grigoryeva E, Pigozzo J. Evaluation of Two Dosing Regimens for Nivolumab in Combination With Ipilimumab in Patients With Advanced Melanoma: Results From the Phase IIIb/IV CheckMate 511 Trial. J Clin Oncol. 2019 Apr 10;37(11):867-875. doi: 10.1200/JCO.18.01998. Epub 2019 Feb 27.
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Nevi and Melanomas
- Melanoma
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Immune Checkpoint Inhibitors
- Nivolumab
- Azacitidine
- Ipilimumab
- Guadecitabine
Other Study ID Numbers
- NIBIT-ML1
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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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