Back to resultsA Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients (NIBIT-M4)
Primary Purpose
Metastatic Melanoma
Status
Unknown status
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
SGI-110
Ipilimumab
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Melanoma focused on measuring melanoma, ipilimumab, SGI-110
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.
Sites / Locations
- Medical Oncology and Immunotherapy Unit, University Hospital of SienaRecruiting
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
SGI-110 and Ipilimumab
Arm Description
SGI-110 in combination with Ipilimumab
Outcomes
Primary Outcome Measures
Maximum Tolerated Dose (MTD) of SGI-110 in combination with ipilimumab
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.
Secondary Outcome Measures
Immune-related Disease Control Rate (irDCR)
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)
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)
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)
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)
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.
Full Information
NCT ID
NCT02608437
First Posted
November 13, 2015
Last Updated
November 16, 2015
Sponsor
Italian Network for Tumor Biotherapy Foundation
Collaborators
Astex Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02608437
Brief Title
A Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients
Acronym
NIBIT-M4
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
2. Study Status
Record Verification Date
November 2015
Overall Recruitment Status
Unknown status
Study Start Date
October 2015 (undefined)
Primary Completion Date
October 2016 (Anticipated)
Study Completion Date
October 2018 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Italian Network for Tumor Biotherapy Foundation
Collaborators
Astex Pharmaceuticals, Inc.
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Melanoma
Keywords
melanoma, ipilimumab, SGI-110
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
19 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
SGI-110 and Ipilimumab
Arm Type
Experimental
Arm Description
SGI-110 in combination with Ipilimumab
Intervention Type
Drug
Intervention Name(s)
SGI-110
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Ipilimumab(Yervoy)
Intervention Description
ipilimumab: 3 mg/Kg i.v. over 90 minutes on W1, 4, 7 and 10 for a total of 4 cycles.
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose (MTD) of SGI-110 in combination with ipilimumab
Description
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.
Time Frame
the first 3 weeks of treatment
Secondary Outcome Measure Information:
Title
Immune-related Disease Control Rate (irDCR)
Description
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.
Time Frame
weeks 24
Title
Immune-related Objective Response Rate (irORR)
Description
Immune-related Objective Response Rate (irORR) is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.
Time Frame
weeks 24
Title
Immune-related Time to Response (irTTR)
Description
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).
Time Frame
weeks 24
Title
Immune-related Duration of Response (irDoR)
Description
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.
Time Frame
2 years
Title
Immune-related progression free survival (irPFS)
Description
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.
Time Frame
2 years
Other Pre-specified Outcome Measures:
Title
Phenotypic/epigenetic profile of tumor samples and peripheral blood mononuclear cells
Description
Changes in the immune phenotype/epigenetic profile of neoplastic cells and of immune cells.
Time Frame
2 years
Title
humoral immune responses induced by treatment
Description
Changes in the humoral and cellular immune responses induced by treatment will be investigated utilizing standardized and validated techniques.
Time Frame
2 years
Title
Maximum Plasma Concentration [Cmax] of of SGI-110 and decitabine.
Description
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.
Time Frame
24 hours
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anna Maria Di Giacomo, PhD,MD
Phone
+390577586305
Email
a.m.digiacomo@ao-siena.toscana.it
First Name & Middle Initial & Last Name or Official Title & Degree
Michele Maio, PhD,MD
Phone
+390577586335
Email
mmaiocro@gmail.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anna Maria Di Giacomo, PhD,MD
Organizational Affiliation
Medical Oncology and Immunotherapy Unit, University Hospital of Siena
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medical Oncology and Immunotherapy Unit, University Hospital of Siena
City
Siena
ZIP/Postal Code
53100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anna Maria Di Giacomo, PhD, MD
Phone
+390577586305
Email
a.m.digiacomo@ao-siena.toscana.it
First Name & Middle Initial & Last Name & Degree
Giovanni Amato, PhD
Phone
+390577586326
Email
dataman.immonco@ao-siena.toscana.it
12. IPD Sharing Statement
Citations:
PubMed Identifier
23299197
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.
Results Reference
background
PubMed Identifier
25965370
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.
Results Reference
background
PubMed Identifier
16882708
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.
Results Reference
result
Links:
URL
http://www.fondazionenibit.org/
Description
Fondazione NIBIT
Learn more about this trial
A Study Investigating SGI-110 in Combination With Ipilimumab in Unresectable or Metastatic Melanoma Patients
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