| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.0 |
| E.1.2 | Level | VTc |
| E.1.2 | Classification code | 10025650 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare overall survival for patients with advanced melanoma who are randomized toreceive ticilimumab with that of patients who are randomized to receive eitherdacarbazine or temozolomide. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives:To compare durable response rate, 6-month progression-free survival, to assess objective response rate for patients,to assess duration of response, assess time to worsening of ECOG performance status, to further characterize the safety profile and toleration of ticilimumab, to characterize any human antihuman antibody (HAHA) response to ticilimumab, to compare health related quality of life (HQoL) outcomes, to compare patient reported healthcare resource utilization and loss of productivity in the 2 treatment arms, to explore any relationship between ticilimumab exposure, measured as Cmax and C4wk, and clinical response in this population in the two treaent arms. To explore whether the CTLA4, FcgammaRIIa and IgG2a genotypes influence the safety and/or efficacy of patients treated with ticilimumabTo explore relationships between clinical response (efficacy or toxicity) and tumor or blood genomics |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the trial:
1. Histologically confirmed melanoma that is not surgically curable and is either:
• Stage IV (AJCC 6th edition) OR
• Stage IIIC (AJCC 6th edition) with N3 status for regional lymph nodes and in-transit or satellite lesions
NOTE: Patients with mucosal melanoma will not be excluded. All HLA types are eligible.
2. Patients must either have measurable disease or have non-measurable disease which can be evaluated for objective response, as defined here:
• Measurable Disease. Patient has at least one lesion that meets the following criteria: Measurable lesions can be accurately measured in at least one dimension. Lesions on CT scan must have longest diameter 2.0 cm using conventional techniques or 1.0 cm with spiral CT scan. Skin lesions documented by photography must have longest diameter at least 1.0 cm. Clinically detected lesions must be superficial (eg, skin nodules), and the longest diameter must be 2.0 cm. Palpable lymph nodes >2.0 cm should be demonstrable by CT scan. If the measurable disease is restricted to a solitary lesion, its neoplastic nature must be confirmed by cytology or histology. Tumor lesions that are situated in a previously irradiated area will be considered measurable only if progression is documented following completion of radiation therapy.
• Non-Measurable Disease. Patients with non-measurable disease (ie, without lesions that meet the above criteria for measurability) must have evidence of disease confirmed by pathology (ie, needle aspirate/biopsy). Patients with previously irradiated lesions must have documented progression or disease outside the radiation port.
3. ECOG performance status of 0 or 1
4. Age 18 years or older
5. Adequate bone marrow, hepatic, and renal function determined within 14 days prior to randomization, defined as:
• Absolute neutrophil count 1.5 x 109 cells/L
• Platelets >100 x 109/L
• Hemoglobin >10 g/dL
• Aspartate and alanine aminotransferases (AST, ALT) <2.5 x Upper Limit of Normal (ULN), or <5 x ULN, if documented liver metastases are present
• Total serum bilirubin <2 x ULN (except patients with documented Gilbert’s syndrome)
• Serum creatinine <2.0 mg/dL or calculated creatinine clearance <60 mL/min
6. Serum lactic acid dehydrogenase (LDH) <2 x ULN
7. CT scan of the brain with contrast or MRI of the brain within 28 days of enrollment showing no evidence of brain metastases
8. Patients must have recovered from all prior surgical or adjuvant treatment-related toxicities, to baseline status, or a CTC Grade of 0 or 1, except for toxicities not considered a safety risk, such as alopecia. Post surgical pain will not be considered a basis for exclusion.
9. Females of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to randomization. Females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential.
10. Females of childbearing potential and males who have not undergone surgical sterilization must agree to practice a form of effective contraception prior to entry into the study and for 12 months (females) or 6 months (males) following the last dose of study drug. The definition of effective contraception will be based on the judgment of the investigator.
11. Patient must be willing and able to provide written informed consent.
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| E.4 | Principal exclusion criteria |
Patients presenting with any of the following will not be included in the trial:
1. Melanoma of ocular origin (uveal melanoma)
2. Received any systemic therapy for metastatic melanoma except post-surgical adjuvant treatment with cytokines (eg, alfa-interferon or GM-CSF) or with vaccines after complete resection of melanoma. Patients who received adjuvant cytokine therapy must be at least 30 days from the last dose. Patients who received adjuvant vaccine therapy must be at least 6 months from the last dose. (See Appendix F for a list of cancer vaccines). All patients who received adjuvant therapy must have documented tumor progression since the last dose. Note: Prior chemotherapy or biochemotherapy, including isolated limb perfusion therapy is not allowed. Prior resection for Stage III or Stage IV disease is allowed as long as the patient has unresectable lesions at the time of randomization. Patients who received intradermal BCG for adjuvant therapy for Stage III or IV melanoma are not excluded.
3. History of brain metastases
4. Received any prior CTLA4 inhibiting agent (eg MDX-010)
5. Patients previously randomized on this protocol
6. History of chronic autoimmune disease (eg, Addison’s disease, multiple sclerosis, Graves’ disease, Hashimoto’s thyroiditis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, hypophysitis, etc.). Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.
7. History of uveitis or melanoma-associated retinopathy
8. History of inflammatory bowel disease (eg, Crohn’s disease or ulcerative colitis), celiac disease, or other chronic gastrointestinal conditions associated with diarrhea, or current acute colitis of any origin
9. Known active or chronic viral hepatitis
10. Any serious uncontrolled medical disorder or active infection that would impair the patient’s ability to receive study treatment. Note: Patients with Acquired Immunodeficiency Syndrome (AIDS) are excluded.
11. Received an immunosuppressive dose of corticosteroids or other immunosuppressive medication (eg, methotrexate, rapamycin) within 30 days of randomization. Note: Patients with adrenal insufficiency may take up to 5 mg of prednisone or equivalent daily. Topical and inhaled corticosteroids in standard doses are allowed.
12. History of other malignancy, except for adequately treated basal cell carcinoma or squamous cell skin cancer or carcinoma in situ of the cervix, unless the patient has been disease-free for at least 5 years
13. Breast-feeding
14. Dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of this protocol
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| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| health related quality of life (HqoL) outcomes |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
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