| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| 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 correlate pre-treatment characteristics of the patient and/or tumor with clinical tumor response in patients with unresectable Stage III and IV melanoma, in order to identify candidate markers predictive of response and/or serious toxicity to ipilimumab dosed at 3 or 10 mg/kg q 3 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
*Evaluate BORR in this pt population receiving respective ipilimumab doses of 3 mg/kg & 10 mg/kg
*Estimate in this pt population receiving resp ipilimumab doses of 3mg/kg & 10mg/kg:a)Disease control rate b)PFS rate at Week 12 c)PFS d)Overall survival e)Survival rate at 1 year f)Duration of response & proportion of pts whose duration of response is ≥24 weeks g)Time to response
*Evaluate safety of ipilimumab in this pt population receiving resp. ipilimumab doses of 3mg/kg & 10mg/kg
*Estimate sensitivity & specificity of any candidate marker or combination of markers for prediction of clinical response &/or serious toxicity to ipilimumab
*Compare mRNA, protein & microscopic profiles in pre& post trt tumor specimens in pts treated with ipilimumab at 3 or 10 mg/kg q3 weeks x4
*Compare DTH response, antibody response, peripheral blood mRNA expression & PBMC functional attributes pre& post trt in pts treated with ipilimumab at 3 or 10 mg/kg q3 weeks x4
See protocol for other sec. obj.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Target population
a) Able to comply with visits/procedures required by the protocol
b) Life expectancy of at least 4 months.
c) ECOG performance status score 0-1. (See Appendix 4 of the protocol)
d) Histologic or cytologic diagnosis of unresectable Stage III or IV malignant
melanoma (excluding ocular melanoma).
e) A pre- and post-treatment fresh core or excision tumor biopsy must be provided
for biomarker and predictive marker analyses. It is preferred that the biopsies are
obtained from the same organ. Note: Site of tumor biopsy should not be the only
site of measurable disease.
f) Measurable disease as defined in Section 3.3.2.2 of the protocol.
g) Required values for initial laboratory tests (see protocol for test details)
h) At least 4 weeks must have elapsed since the last chemotherapy, immunotherapy,
hormonal therapy, radiotherapy or major surgery and the beginning of protocol
therapy. At least 6 weeks for nitrosoureas, mitomycin C and liposomal doxorubicin.
i) Toxicity related to prior therapy must either have returned to ≤ grade 1, baseline,
or been deemed irreversible.
3) Age and Sex
a) Men and women, ages 18 and above.
• Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study in such a manner that the
risk of pregnancy is minimized. Suggested precautions should be
used to minimize the risk or pregnancy for at least 1 month before dosing, and
while women are on study and for up to 12 weeks after last dose of study drug.
• WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation
or bilateral oophorectomy) or is not postmenopausal [defined as amenorrhea
≥ 12 consecutive months; or women on hormone replacement therapy (HRT) with
documented serum follicle stimulating hormone (FSH) level > 35mIU/mL]. Even women who are using oral, implanted or injectable contraceptive hormones or
mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child bearing potential.
• WOCBP must have a negative pregnancy test (minimum sensitivity 25 IU/L or
equivalent units of HCG) within 72 hours prior to the start of study medication.
• Men must be willing and able to use an acceptable method of birth control, for at
least 3 months after completion of the study, if their sexual partners are WOCBP. |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 12 weeks after the study;
b) WOCBP using a prohibited contraceptive method;
c) Women who are pregnant or breastfeeding;
d) Women with a positive pregnancy test on enrollment or prior to study drug administration;
e) Sexually active fertile men who are unwilling or unable to use an acceptable method of birth control, for the entire study period and for at least 3 months after completion of the study, if their sexual partners are WOCBP.
2) Target Disease Exclusion
a) Any other 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;
b) Ocular melanoma.
3) Medical History and Concurrent Diseases
a) Active, untreated central nervous system (CNS) metastasis (including metastasis
identified during screening MRI or contrast CT);
b) Autoimmune disease: Patients with a history of Inflammatory Bowel Disease are
excluded from this study as are patients with a history of autoimmune disease (e.g. Systemic Lupus Erythematosus, vasculitis, infiltrating lung disease) whose possible progression during treatment would be considered by the Investigator to be unacceptable. Patients with a history of well-controlled and/or clinically manageable autoimmune disease (e.g. vitiligo, well-controlled thyroid disease, mild psoriasis) may be considered for inclusion in consultation with the BMS Medical Monitor;
c) 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;
d) Positive screening tests for HIV, HepB, and HepC. If positive results are not indicative of true active or chronic infection, the patient can be admitted after discussion with and agreement by the BMS Medical Monitor;
e) Uncontrolled or significant cardiovascular disease including
− myocardial infarction within 12 months
− uncontrolled angina within 6 months
− Class III-IV New York Heart Association (NYHA) congestive heart failure
− diagnosed or suspected congenital long QT syndrome
− any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or torsade de pointes). Any
patient with a history of any arrhythmia should be discussed with the BMS Medical Monitor prior to entry into the study
− prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)
− any history of second or third degree heart block (may be eligible if currently have a pacemaker)
4) Prohibited Therapies and/or Medications
a) Prior exposure to an anti-CTLA4 antibody.
b) Use of any immunosuppressing treatments including corticosteroids (patients on
stable doses of hormone replacement therapy are exempt), cyclosporine, mycophenolate mofetil (CellCept), chemotherapy, radiation, etc, within 4 weeks
prior to Day 1 of treatment.
c) Exposure to any investigational drug or placebo within 4 weeks prior to Day 1 of
treatment.
d) Drugs that are generally accepted to have a risk of causing Torsade de Pointes
(see Appendix 7). Patients who have discontinued any of these medications must
have a wash-out period of at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior to the first dose of MDX-010 (BMS-734016).
e) Concomitant therapy with any of the following: IL-2, interferon or other non-study anti-melanoma immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigational therapies; or chronic use of
systemic corticosteroids (patients on stable doses of hormone replacement therapy
are exempt.
f) While there is no limit to prior chemotherapy, concomitant chemotherapy is
prohibited.
5) Other Exclusion Criteria
a) Prisoners or patients who are compulsorily detained (involuntarily incarcerated)
for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy Analyses:
The primary efficacy analysis will be performed when the last randomized patient has
been followed to Week 24. The primary efficacy analysis will be based on BORR with
the corresponding two-sided exact 95% CI.
Best overall response subgroup analyses will be performed by the following variables: age (<65, >65), race (White, Black, Asian, Other), gender (male, female), M stage(M0 vs. M1a vs. M1b vs. M1c), prior therapy with IL-2 or dacarbazine-containing regimens (yes vs. no), prior therapy with cancer vaccines (yes vs. no), baseline performance status (0 vs. 1), and emergence of immune breakthrough events (yes vs. no).
Disease control rate and major durable response rate, will be calculated along with
corresponding exact two-sided 95% CI.
PFS, OS, Time to Response for all treated patients, and Duration of Response will be
calculated using Kaplan-Meier estimates, and medians with corresponding two-sided
95% confidence intervals will be reported. Time to Response will also be summarized for patients with BOR of CR or PR, using descriptive statistics.
PFS rate at Week 12 will be calculated both using the Kaplan-Meier method along with a corresponding two-sided CI, and as a proportion along with a corresponding exact two-sided 95% CI.
Survival rate at one year will be calculated using the Kaplan-Meier method along with a corresponding two-sided CI.
Safety Analyses:
The analysis of safety will be based on the frequency of adverse events and their severity for all treated patients. Worst toxicity grades per patient will be tabulated for adverse events and laboratory measurements by using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (CTCAE).
|
|
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The primary analysis will be performed when the last randomized patient has been followed to the tumor re-staging assessment at Week 24. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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