A Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients (NIBIT-M4)

• ClinicalTrials.gov Identifier: NCT02608437
• Recruitment Status: Unknown
• First Posted: November 18, 2015
• Last Update Posted: November 18, 2015
• Sponsor: Italian Network for Tumor Biotherapy Foundation
• Collaborator: Astex Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Italian Network for Tumor Biotherapy Foundation

Tracking Information

• First Submitted Date: November 13, 2015
• First Posted Date: November 18, 2015
• Last Update Posted Date: November 18, 2015
• Study Start Date: October 2015
• Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 16, 2015)

Maximum Tolerated Dose (MTD) of SGI-110 in combination with ipilimumab [ Time Frame: the first 3 weeks of treatment ]

The primary objective is to determine the MTD of SGI-110 in combination with ipilimumab in 21 day cycles in melanoma patients. Endpoints related to this objective include an evaluation of Dose Limiting Toxicity(s). The MTD evaluation will be based on the DLT evaluable population.

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: November 16, 2015)

• Immune-related Disease Control Rate (irDCR) [ Time Frame: weeks 24 ]
  Immune-related Disease Control Rate (irDCR) is the proportion of treated subjects with an immune-related Best Overall Responce (ir-BOR) of confirmed irCR, confirmed irPR or irSD.
• Immune-related Objective Response Rate (irORR) [ Time Frame: weeks 24 ]
  Immune-related Objective Response Rate (irORR) is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.
• Immune-related Time to Response (irTTR) [ Time Frame: weeks 24 ]
  Immune-related Time to Response (irTTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).
• Immune-related Duration of Response (irDoR) [ Time Frame: 2 years ]
  Immune-related Duration of Response (irDoR) for the subjects whose irBOR is irCR or irPR will be defined as the time between the date of response of confirmed irCR or confirmed irPR (whichever occurs first) and the date of irPD or death (whichever occurs first). The onset of a confirmed irCR or irPR is determined by the initial assessment of response, not by the confirmatory assessment. Note that if an assessment of irPR occurs before confirmation of irCR, the duration of immune-related response endpoint will not begin at the time that the irBOR of irCR is shown but rather at the earlier time-point showing irPR. For subjects who remain alive and have not progressed following response, irDoR will be censored on the date of last evaluable Tumor Assessment.
• Immune-related progression free survival (irPFS) [ Time Frame: 2 years ]
  Immune-related progression free survival (irPFS) per irRC will be defined as the time between the date of randomization and the date of progression per irRC or death, whichever occurs first. A subject who dies without reported progression per irRC will be considered to have progressed on the date of death. For those subjects who remain alive and have not progressed, irPFS will be censored on the date of last evaluable Tumor Assesment. For those subjects who remain alive and have no recorded post baseline Tumor Assessment, irPFS will be censored on the day of last clinical evaluation.

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: November 16, 2015)

• Phenotypic/epigenetic profile of tumor samples and peripheral blood mononuclear cells [ Time Frame: 2 years ]
  Changes in the immune phenotype/epigenetic profile of neoplastic cells and of immune cells.
• humoral immune responses induced by treatment [ Time Frame: 2 years ]
  Changes in the humoral and cellular immune responses induced by treatment will be investigated utilizing standardized and validated techniques.
• Maximum Plasma Concentration [Cmax] of of SGI-110 and decitabine. [ Time Frame: 24 hours ]
  Plasma samples will be prepared from blood drawn at the following time-points: Cycle 1, Day 1: pre-dose, 15 min, 30 min, 60 min, 90 min, 2 hr, 4 hr, 6 hr and 8 hr post-dose.

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: A Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients
• Official Title: A Phase 1b, Open-label, Dose Escalation Study Investigating Different Doses of SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients
• Brief Summary: Thi pahse I, dose-escalation trial will determine the MTD, safety and the additional benefit achieved from adding SGI-110 to ipilimumab therapy in metastatic melanoma patients. Preclinical evidence generated with SGI-110 in vivo demonstrated that besides having a direct activity on tumor growth as a single agent, SGI-110 was able to "sensitize" neoplastic cells to the anti-tumor activity of CTLA-4 blockade, providing a sound scientific rationale to develop new immunotherapeutic approaches combining SGI-110 with therapeutic mAb to immune check-points.

Detailed Description

Epigenetic alterations play a pivotal role in cancer development and progression. Pharmacologic reversion of such alterations is feasible, and 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 us 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 antibody (mAb) 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 metastatic melanoma (MM), significantly improving the survival of MM patients; however, objective clinical responses are limited, and only a minority of patients achieves long-term disease control.1 Therefore, several combination approaches are being explored to improve the efficacy of CTLA-4 blockade. Along this line, based on the preclinical evidence the investigators gained on the broad immunomodulatory activity of SGI-110, the exploratory phase 1 combination study NIBIT-M4 has been designed to provide proof-of-concept evidence to the immunologic and clinical efficacy of CTLA-4 blockade combined with DNA-HypomethylatingAgent (DHA). Progressing Stage III or Stage IV MM patients, amenable to serial tumor biopsies will be enrolled in the study.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Melanoma

Intervention

• Drug: SGI-110
  SGI-110: start at 30 mg/m2 s.c. on W0, 3, 6, 9 Day 1 - 5 q21 days. Dose level -1: 15 mg/m2; dose level +1: 45 mg/m2
• Drug: Ipilimumab
  ipilimumab: 3 mg/Kg i.v. over 90 minutes on W1, 4, 7 and 10 for a total of 4 cycles.
  Other Name: Ipilimumab(Yervoy)

Study Arms

Experimental: SGI-110 and Ipilimumab

SGI-110 in combination with Ipilimumab

Interventions:

• Drug: SGI-110
• Drug: Ipilimumab

Publications *

• 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.
• 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.
• Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'Brien S, Cortes J, Faderl S, Bueso-Ramos C, Ravandi F, Estrov Z, Ferrajoli A, Wierda W, Shan J, Davis J, Giles F, Saba HI, Issa JP. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007 Jan 1;109(1):52-7. doi: 10.1182/blood-2006-05-021162. Epub 2006 Aug 1.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: November 16, 2015): 19
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 2018
• Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Willing and able to give written informed consent
• Unresectable Stage III or Stage IV melanoma with measurable lesions by CT or MRI per mWHO/irRC criteria, that can be amenable to biopsy
• Previously treated or untreated; prior therapy may include chemotherapy or targeted therapy for metastatic disease (i.e., BRAF and/or MAP-ERK kinase (MEK) inhibitor). Prior adjuvant interferon is permitted
• Subjects with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
• 4 weeks or greater since last treatment
• Must have recovered from any acute toxicity associated with prior therapy
• Life expectancy greater than 16 weeks
• Negative screening tests for HIV, Hepatitis B, and Hepatitis C
• 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 SGI-110 + 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:

• Subjects with any contraindications for ipilimumab
• Subjects with active brain metastases or leptomeningeal metastases
• Subjects with metastatic uveal melanoma
• Subjects with active, known or suspected autoimmune disease
• Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of treatment
• Subjects with symptomatic effusions on account of pleural, pericardial metastases of melanoma
• Prior treatment with an anti-Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-CTLA-4 antibody
• Subjects who had major surgery or radiation therapy within 21 days of starting treatment
• Subjects who are unable to return for follow-up visits as required by this study

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT02608437
• Other Study ID Numbers: NIBIT-M4
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Italian Network for Tumor Biotherapy Foundation
• Original Responsible Party: Same as current
• Current Study Sponsor: Italian Network for Tumor Biotherapy Foundation
• Original Study Sponsor: Same as current
• Collaborators: Astex Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Anna Maria Di Giacomo, PhD,MD; Medical Oncology and Immunotherapy Unit, University Hospital of Siena

• PRS Account: Italian Network for Tumor Biotherapy Foundation
• Verification Date: November 2015