Clinical trial NCT02608437: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Metastatic Melanoma
Keywords: melanoma
ipilimumab
SGI-110
Lead sponsor: Italian Network for Tumor Biotherapy Foundation
Sponsor class: OTHER
Collaborators: name: Astex Pharmaceuticals, Inc.
First posted: 2015-11-18
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of SGI-110 in combination with ipilimumab
timeFrame: the first 3 weeks of treatment
Secondary outcomes:
measure: Immune-related Disease Control Rate (irDCR)
timeFrame: weeks 24
measure: Immune-related Objective Response Rate (irORR)
timeFrame: weeks 24
measure: Immune-related Time to Response (irTTR)
timeFrame: weeks 24
measure: Immune-related Duration of Response (irDoR)
timeFrame: 2 years
measure: Immune-related progression free survival (irPFS)
timeFrame: 2 years
Other outcomes:
measure: Phenotypic/epigenetic profile of tumor samples and peripheral blood mononuclear cells
timeFrame: 2 years
measure: humoral immune responses induced by treatment
timeFrame: 2 years
measure: Maximum Plasma Concentration [Cmax] of of SGI-110 and decitabine.
timeFrame: 24 hours
Locations:
city: Siena
country: Italy
facility: Medical Oncology and Immunotherapy Unit, University Hospital of Siena
Study officials:
affiliation: Medical Oncology and Immunotherapy Unit, University Hospital of Siena
name: Anna Maria Di Giacomo, PhD,MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.