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

Italian Network for Tumor Biotherapy Foundation

Status and phase

Unknown

Phase 1

Conditions

Metastatic Melanoma

Treatments

Drug: SGI-110

Drug: Ipilimumab

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT02608437

NIBIT-M4

Details and patient eligibility

About

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.

Full 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.

Enrollment

19 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.