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

NCT04250246 | Unknown Phase 2 DMC

• 1 other identifier: NIBIT-ML1
• Study Type: interventional
• Target: 184
• Locations: 1 country
• Sites: 1

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.

Conditions

Melanoma; Non Small Cell Lung Cancer

Keywords

melanoma; NSCLC; ipilimumab; nivolumab; guadecitabine

Outcome Measures

Primary Outcomes (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.

  24 weeks

Secondary Outcomes (7)

• Safety of guadecitabine in combination with ipilimumab and nivolumab

  2 years

• Obiective Response Rate (ORR)

  24 weeks

• Disease Control Rate (DCR)

  24 weeks

• Duration of response (DoR)

  2 years

• Time to response (TTR)

  24 weeks

Study Arms (2)

Ipilimuamb plus nivoluamb plus guadecitabine

EXPERIMENTAL

ipilimumab plus nivolumab combined with guadecitabine

Drug: Ipilimumab plus nivolumab plus guadecitabine

Ipilimumab plus nivolumab

ACTIVE COMPARATOR

Ipilimumab plus nivolumab

Drug: Ipilimumab plus nivolumab

Interventions

Ipilimumab plus nivolumab plus guadecitabine DRUG

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

Also known as: ipilimumab (Yervoy), nivolumab (Opdivo), guadecitabine (SGI-110)

Ipilimuamb plus nivoluamb plus guadecitabine

Ipilimumab plus nivolumab DRUG

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.

Also known as: ipilimumab (Yervoy), nivolumab (Opdivo)

Ipilimumab plus nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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);

Sponsors & Collaborators

• Italian Network for Tumor Biotherapy Foundation: lead
• Astex Pharmaceuticals, Inc.: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (1)

Center for Immuno-Oncology, University Hospital of Siena

Siena, 53100, Italy

Location

Related Publications (10)

• 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.

  PMID: 26398076 BACKGROUND

• 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.

  PMID: 27718847 BACKGROUND

• 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.

  PMID: 23299197 BACKGROUND

• 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.

  PMID: 26374074 BACKGROUND

• 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.

  PMID: 24384533 BACKGROUND

• 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.

  PMID: 31530631 BACKGROUND

• 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.

  PMID: 25965370 BACKGROUND

• 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.

  PMID: 30361170 BACKGROUND

• 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.

  PMID: 30785829 BACKGROUND

• 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.

  PMID: 30811280 BACKGROUND

Related Links

• Fondazione NIBIT Onlus Network Italiano per la Bioterapia dei Tumori

MeSH Terms

Conditions

Melanoma; Carcinoma, Non-Small-Cell Lung

Interventions

Ipilimumab; Nivolumab; guadecitabine

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Anna Maria Di Giacomo, MD

  Center for Immuno-Oncology, University Hospital of Siena

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Anna Maria Di Giacomo, MD

CONTACT

+390577586338; a.m.digiacomo@ao-siena.toscana.it

Michele Maio, MD PhD

CONTACT

+390577586335; mmaiocro@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, non-comparative, phase II study designed according to a two stages optimal design by Simon

Study Record Dates

• First Submitted: January 23, 2020
• First Posted: January 31, 2020
• Study Start: March 1, 2020
• Primary Completion: March 1, 2023
• Study Completion: March 1, 2025
• Last Updated: January 31, 2020

Record last verified: 2020-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)