A Combination of Ipilimumab and Fotemustine for Treat Unresectable Locally Advanced or Metastatic Melanoma

Metastatic Malignant Melanoma Clinical Trial

— NIBIT-M1  

Official title:

A Phase II Study of the Combination of Ipilimumab and Fotemustine in Patients With Unresectable Locally Advanced or Metastatic Malignant Melanoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01654692
• Other study ID #: NIBIT-M1
• Secondary ID: 2010-019356-50
• Status: Completed
• Phase: Phase 2
• First received: July 18, 2012
• Last updated: May 12, 2015
• Start date: June 2010
• Est. completion date: September 2014

Study information

• Verified date: May 2015
• Source: Italian Network for Tumor Biotherapy
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial Summary

This study is designed to assess the safety and efficacy of a combination of ipilimumab and fotemustine in Patients with Unresectable Locally Advanced or Metastatic Malignant Melanoma.

Description:

Immunotherapy, chemotherapy and chemotherapy combinations are currently the most effective accepted systemic treatments for metastatic melanoma. However, significant and prolonged responses are rare.

The trial will determine the additional benefit achieved from adding fotemustine to the anti-CTLA-4 monoclonal antibody,ipilimumab .

It is assumed that the mechanism by which ipilimumab augments the effects of chemotherapy in animal models relies on the ability of the cytotoxic agent to induce apoptosis of tumor cells. These apoptotic cells then can function as potent inducers of an immune response against any non-tolerized antigen that they contain. Thus, the chemotherapy may be creating an in vivo autologous tumor vaccine. Ipilimumab prevents the down regulation of this immune response, allowing for tumor rejection. Animal models evaluating the combination of anti-CTLA4 antibody and chemotherapy have given only a brief acute treatment with chemotherapy - presumably adequate to induce some tumor apoptosis, but inadequate to induce significant prolonged tumor rejection.

Since patients with metastatic melanoma generally require therapy within a relatively short period of time, this protocol will allow for the use of fotemustine. Standard dosing of fotemustine will be used to optimize the chance for tumor control.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: September 2014
• Est. primary completion date: May 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologic diagnosis of malignant melanoma

• Stage III (unresectable) or Stage IV melanoma

• Maximum 1 line of chemotherapy for advanced disease allowed

• No prior chemotherapy within 4 weeks from treatment start (6 weeks in case of nitrosourea)

• No previous systemic corticosteroid therapy within 10 days

• Prior adjuvant treatment with IFN or other immunotherapy allowed

• Asymptomatic brain metastases allowed

• Measurable disease

• Prior treatment of brain metastases. In case stereotactic radiotherapy (or surgery) was not applicable, whole brain radiotherapy should have been performed

• Life expectancy >= 16 weeks

• ECOG performance status of 0 or 1

• Normal laboratory tests were required

• Negative screening tests for HIV, Hepatitis B, and Hepatitis C.

• Men and women, of and over 18 years old. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the study in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

• Any malignancy from which the patient has been disease-free for less than 5 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix;

• Primary ocular or mucosal melanoma. Medical History and Concurrent Diseases

• Symptomatic brain metastases requiring immediate local intervention (radiotherapy (RT) and/or surgery)

• Autoimmune disease

• Any underlying medical condition, which in the opinion of the investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.

Prohibited Treatments and/or Therapies

• Concomitant therapy with any anti-cancer agent

• Immunosuppressive agents

• Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1 month prior to or after any dose of study drug); surgery or radiotherapy ; other investigational anti-cancer therapies; or chronic use of systemic corticosteroids ;

• Previous treatment with other investigational products, including cancer immunotherapy, within 30 days;

• Previous enrollment in another clinical trial or prior treatment with a CD137 agonist or anti-CTLA-4 and/or fotemustine.

Sex and Reproductive Status

• WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the study;

• Women who are pregnant or breastfeeding;

• Women with a positive pregnancy test on enrollment or prior to investigational product administration;

• Sexually active fertile men not using effective birth control if their partners are WOCBP.

Other Exclusion Criteria

• Prisoners or subjects who are involuntarily incarcerated;

• Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Melanoma
• Metastatic Malignant Melanoma

Intervention

Drug:
• Ipilimumab and Fotemustine
Ipilimumab: 10 mg/kg q3 weeks for 4 doses, q12 weeks starting at Week 24 Fotemustine: 100 mg/m2 q1 week for 3 doses, q3 weeks starting at Week 9

Locations

Country	Name	City	State
Italy	National Institute for Cancer Research	Genoa
Italy	Immunotherapy and Somatic Cell Therapy Unit, Scientific Institute of Romagna	Meldola
Italy	European Institute of Oncology	Milan
Italy	Melanoma Unit, San Raffaele Hospital	Milan
Italy	Surgical Oncology, National Cancer Institute	Milan
Italy	Medical Oncology and Innovative Therapy, National Cancer Institute	Naples
Italy	Medical Oncology and Immunotherapy-University Hospital of Siena	Siena

Sponsors (2)

Lead Sponsor	Collaborator
Italian Network for Tumor Biotherapy	Bristol-Myers Squibb

Country where clinical trial is conducted

Italy, 

References & Publications (4)

Avril MF, Aamdal S, Grob JJ, Hauschild A, Mohr P, Bonerandi JJ, Weichenthal M, Neuber K, Bieber T, Gilde K, Guillem Porta V, Fra J, Bonneterre J, Saïag P, Kamanabrou D, Pehamberger H, Sufliarsky J, Gonzalez Larriba JL, Scherrer A, Menu Y. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol. 2004 Mar 15;22(6):1118-25. — View Citation

Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi: 10.1056/NEJMoa1003466. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep 23;363(13):1290. — View Citation

Margolin K, Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, Wolchok JD, Clark JI, Sznol M, Logan TF, Richards J, Michener T, Balogh A, Heller KN, Hodi FS. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012 May;13(5):459-65. doi: 10.1016/S1470-2045(12)70090-6. Epub 2012 Mar 27. — View Citation

Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26. doi: 10.1056/NEJMoa1104621. Epub 2011 Jun 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The immune response disease control rate (irDCR) using the immune-related (ir) tumor response criteria of the combination of ipilimumab and fotemustine in patients with unresectable locally advanced or metastatic melanoma.	Immune-related Disease Control Rate (irDCR) is the proportion of treated subjects with a BOR of confirmed irCR, confirmed irPR or irSD.; Tumor assessment (including determination of overall response at each tumor assessment and best overall response (BOR) taken over all tumor assessments prior to subsequent therapy is performed using the immune-related (ir) tumor response criteria.	Weeks 24	No
Secondary	safety and feasibility of the combination of ipilimumab and fotemustine	A first clinical safety assessment will be performed to identify any early safety signals from ipilimumab given in combination with fotemustine at the first 18 treated patients. All subjects who receive at least 1 dose of study drug will be evaluable for safety parameters. Additionally, any occurrence of a SAE from time of consent forward will be reported.	2 years	Yes
Secondary	Immune-related Major Durable Disease Control Rate (irMDDCR)	Immune-related Major Durable Disease Control Rate (irMDDCR) is the proportion of treated subjects with a duration of disease control of >= 24 weeks measured from Week 12, or (for those subjects with a confirmed irCR or confirmed irPR prior to Week 12) from the date of first overall response of irCR or irPR, until the date of irPD or death (whichever occurs first).	up to 24 weeks	No
Secondary	Immune-related Objective Response Rate (irORR)	Immune-related Objective Response Rate (irORR) is the proportion of treated subjects with a BOR of confirmed irCR or confirmed irPR.	Weeks 24	No
Secondary	Immune-related Time to Response (irTTR)	irTTR is defined as the time from first dosing date until the measurement criteria (using irRC) are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).	Weeks 24	No
Secondary	Immune-related Progression-Free Survival (irPFS)	Immune-related Progression-Free Survival (irPFS) is defined as the time between the first dosing date and the date of irPD, or date of death, whichever occurs first. (ie, subjects who die without reported irPD will be considered to have progressed on the date of death).	2 years	No
Secondary	Brain Progression-free Survival (Brain-PFS)	Brain Progression-free Survival (Brain-PFS) is defined as the time from first dosing date to the date of progression as per MRI of existing brain lesions, or of occurrence as per MRI of a new lesion located in the brain, or of death.	2 years	No
Secondary	Overall Survival (OS)	Overall Survival (OS) is defined as the time from first dosing date until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.; OS will be further described using the survival rate at one year, defined as the probability that a subject is alive at 1 and 2 years following first dose of study therapy and estimated via the Kaplan-Meier method.	2 years	No

External Links

•   Italian Network for Tumor Biotherapy (NIBIT) web-site, which will allow access to the diverse activities of the Network