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MelanomaPhase 2NIBIT-ML1NCT04250246

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

A Phase 2 study testing Ipilimumab plus nivolumab plus guadecitabine and Ipilimumab plus nivolumab in people with Melanoma and Non Small Cell Lung Cancer, run by Italian Network for Tumor Biotherapy Foundation at 1 site in Italy.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Melanoma, Non Small Cell Lung Cancer
What is being tested?
Ipilimumab plus nivolumab plus guadecitabine and Ipilimumab plus nivolumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
184 participants
Where
1 siteItaly
Study dates
Mar 2020to Mar 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 27Show fewer
  • 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.

Who cannot join

  • 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
Show all 21Show fewer
  • 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
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  • 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.

Trial locations and contacts

1 site in 1 country.

Anna Maria Di Giacomo, MD contact

+390577586338

a.m.digiacomo@ao-siena.toscana.it

Michele Maio, MD PhD contact

+390577586335

mmaiocro@gmail.com

Italy1 site

  • Center for Immuno-Oncology, University Hospital of Siena

    Siena, 53100

    Anna Maria Di Giacomo, MD, +390577586305, a.m.digiacomo@ao-siena.toscana.it

    Giovanni Amato, PhD, +390577586326, dataman.immonco@gmail.com

Other trials in Italy

About this study

Official title: 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)

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.

Read the 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.

Being tested
Ipilimumab plus nivolumab plus guadecitabine, Ipilimumab plus nivolumab
Keywords
melanoma, NSCLC, ipilimumab, nivolumab, guadecitabine
Medical subject headings
Melanoma, Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ipilimumab plus nivolumab plus guadecitabineDrug

    Also called ipilimumab (Yervoy), nivolumab (Opdivo), guadecitabine (SGI-110)

    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

  • Ipilimumab plus nivolumabDrug

    Also called ipilimumab (Yervoy), nivolumab (Opdivo)

    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.

Study groups in NCT04250246
Study groupRoleWhat they receive
Ipilimuamb plus nivoluamb plus guadecitabineExperimentalipilimumab plus nivolumab combined with guadecitabine
Receives: Drug: Ipilimumab plus nivolumab plus guadecitabine
Ipilimumab plus nivolumabActive comparatorIpilimumab plus nivolumab
Receives: Drug: Ipilimumab plus nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Immune-related Objective Response Rate (iORR)

    Immune-related Objective Response Rate (iORR) is the proportion of treated subjects with an iBOR of confirmed iCR or confirmed iPR.

    Measured: 24 weeks

Secondary outcomes (7)

  1. Safety of guadecitabine in combination with ipilimumab and nivolumab

    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

    Measured: 2 years

  2. Obiective Response Rate (ORR)

    Objective Response Rate (ORR) is the proportion of treated subjects with a BOR of CR or PR per RECIST 1.1.

    Measured: 24 weeks

  3. Disease Control Rate (DCR)

    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.

    Measured: 24 weeks

  4. Duration of response (DoR)

    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.

    Measured: 2 years

  5. Time to response (TTR)

    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.

    Measured: 24 weeks

  6. Progression Free Survival (PFS)

    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.

    Measured: 2 years

  7. Overall Survival (OS)

    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.

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted31 Jan 2020
  2. Study startMar 2020 (estimated)
  3. Primary completionMar 2023 (estimated)
  4. Study completionMar 2025 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Randomized, non-comparative, phase II study designed according to a two stages optimal design by Simon
Masking
None (open label)
Enrolment
184 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04250246
Sponsor's protocol ID
NIBIT-ML1
Acronym
NIBIT-ML1
Status last verified
Jan 2020
First submitted
23 Jan 2020
Last updated
31 Jan 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 26398076

  • 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.

    PubMed 27718847

  • 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.

    PubMed 23299197

  • 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.

    PubMed 26374074

  • 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.

    PubMed 24384533

  • 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.

    PubMed 31530631

  • 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.

    PubMed 25965370

  • 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.

    PubMed 30361170

  • 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.

    PubMed 30785829

  • 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.

    PubMed 30811280

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ipilimumab plus nivolumab plus guadecitabine and Ipilimumab plus nivolumab in people with Melanoma and Non Small Cell Lung Cancer, run by Italian Network for Tumor Biotherapy Foundation at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 31 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Anna Maria Di Giacomo, MD (+390577586338, a.m.digiacomo@ao-siena.toscana.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Immune-related Objective Response Rate (iORR) (time frame: 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04250246, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2020.

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