A Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients

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.

Sex

All

Minimum age

18 Years

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.

• BACKGROUNDMaio 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
• BACKGROUNDCovre 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
• RESULTKantarjian 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. PMID 16882708
• DERIVEDNoviello TMR, Di Giacomo AM, Caruso FP, Covre A, Mortarini R, Scala G, Costa MC, Coral S, Fridman WH, Sautes-Fridman C, Brich S, Pruneri G, Simonetti E, Lofiego MF, Tufano R, Bedognetti D, Anichini A, Maio M, Ceccarelli M. Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial. Nat Commun. 2023 Sep 22;14(1):5914. doi: 10.1038/s41467-023-40994-4. PMID 37739939
• DERIVEDAmaro A, Reggiani F, Fenoglio D, Gangemi R, Tosi A, Parodi A, Banelli B, Rigo V, Mastracci L, Grillo F, Cereghetti A, Tastanova A, Ghosh A, Sallustio F, Emionite L, Daga A, Altosole T, Filaci G, Rosato A, Levesque M, Maio M, Pfeffer U, Croce M; EPigenetic Immune-oncology Consortium Airc (EPICA) consortium. Guadecitabine increases response to combined anti-CTLA-4 and anti-PD-1 treatment in mouse melanoma in vivo by controlling T-cells, myeloid derived suppressor and NK cells. J Exp Clin Cancer Res. 2023 Mar 18;42(1):67. doi: 10.1186/s13046-023-02628-x. PMID 36934257