A Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients (NIBIT-M4)
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|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|
- 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.
- 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.
- 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.
|Study Start Date:||October 2015|
|Estimated Study Completion Date:||October 2018|
|Estimated Primary Completion Date:||October 2016 (Final data collection date for primary outcome measure)|
Experimental: SGI-110 and Ipilimumab
SGI-110 in combination with Ipilimumab
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/m2Drug: 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)
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02608437
|Contact: Anna Maria Di Giacomo, PhD,MDfirstname.lastname@example.org|
|Contact: Michele Maio, PhD,MDemail@example.com|
|Medical Oncology and Immunotherapy Unit, University Hospital of Siena||Recruiting|
|Siena, Italy, 53100|
|Contact: Anna Maria Di Giacomo, PhD, MD +390577586305 firstname.lastname@example.org|
|Contact: Giovanni Amato, PhD +390577586326 email@example.com|
|Principal Investigator:||Anna Maria Di Giacomo, PhD,MD||Medical Oncology and Immunotherapy Unit, University Hospital of Siena|