E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with irresectable and metastatic (stage IIIc and IV) melanoma will be randomized to either treatment arm A (ipilimumab) or treatment arm B (TIL) after metastasectomy and feasibility of culturing of TIL. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with metastatic skin cancer will randomly receive either ipilimumab or white blood cells. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025670 |
E.1.2 | Term | Malignant melanoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027481 |
E.1.2 | Term | Metastatic melanoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 progression free survival (according to RECIST 1.1) between patients treated with ipilimumab as compared to patients treated with TIL therapy. |
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E.2.2 | Secondary objectives of the trial |
Progression free survival at 6 months according to RECIST 1.1 and progression free survival according to irRC. Overall response rate according RECIST version 1.1 and irRC, complete response rate, overall survival and safety (according to CTCAE v. 4.0).
To evaluate the impact of the TIL treatment on patient, organizational and economic consequences, a constructive technology assessment will be performed. In this CTA Health Related Quality of Life is evaluated using a questionnaire. Additionally, patient impact of receiving TIL treatment is evaluated by a semi-structured interview with patients receiving TIL treatment and finally the incremental costs per Quality Adjusted Life Year (QALY) gained will be estimated (cost-effectiveness). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Histologically confirmed unresectable AJCC stage IIIc or stage IV melanoma • Patients must have metastatic melanoma with a resectable metastatic lesion(s) of sufficient size (≥ 2-3 cm in total) and must be willing to undergo such a resection for experimental purposes. Resected metastases during stage IV disease that were removed at much earlier time points, but were used to grow clinical grade TIL up to Rapid Expansion Protocol may be used as well with informed consent of the patient. • Patients should have received maximum one line of systemic therapy (except for ipilimumab) for unresectable or metastatic melanoma.[Note that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed at least 6 weeks prior to randomization, and all related adverse events have either returned to baseline or stabilized.] • Patients must be ≥ 18 years and ≤ 75 years of age and must have measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion). • Patients must have a clinical performance status of ECOG 0 or 1 (Appendix B) (38). • Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen. • Patients must be able to understand and sign the Informed Consent document. Laboratory Parameters (Note: patients may undergo resection with lab values outside of the parameters listed below if it is anticipated that the resection will correct the abnormality). • Hematology: - Absolute neutrophil count greater than 1.5 x 109/L without support of filgrastim. - Platelet count greater than 100 x 109/L. - Hemoglobin greater than 5 mmol/L, or 80 g/L. • Chemistry - Serum ALAT/ASAT less than 3 times the upper limit of normal, unless patients have liver metastases (< 5 times ULN). - Serum creatinine clearance 50 ml/min or higher. - Total bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert’s Syndrome who must have a total bilirubin less than 50 micromol/L. - LDH ≤ 2x ULN • Serology: - Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.) - Seronegative for hepatitis B antigen, and hepatitis C antibody. - Seronegative for syphilis. - HSV, EBV, and CMV (positivity for HSV, EBV, or CMV is not an exclusion criterion for participation, but prophylactic medication can be started when deemed necessary prior to chemotherapy treatment in the case patients randomize for the TIL treatment arm).
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E.4 | Principal exclusion criteria |
• Life expectancy of less than three months. • Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma. • Adjuvant treatment with ipilimumab within 6 months prior to randomization. • Requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within the last 3 weeks prior to randomization. • Patients who have more than two CNS metastases. • Patients who have any CNS lesion that is symptomatic, greater than 1 cm in diameter or show significant surrounding edema on MRI scan will not be eligible until they have been treated and demonstrated no clinical or radiologic CNS progression for at least 2 months. • The following patients will be excluded because of inability to receive high dose interleukin-2 (also see Appendix C): - History of coronary revascularization - Documented LVEF of less than 45% in patients with: o Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, 2° or 3° heart block - Documented FEV1 less than or equal to 60% predicted for patients with: o A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years) o Symptoms of respiratory distress • All patients’ toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less. • Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant. • Any active systemic infections, coagulation disorders or other active major medical illnesses. • Any autoimmune disease: patients with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn’s disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, autoimmune thyroiditis (e.g. Hashimoto’s disease), autoimmune hepatitis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (e.g., Wegener’s Granulomatosis). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré Syndrome) are excluded from this study. Patients with vitiligo are eligible to enter the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is progression free survival (according to RECIST 1.1). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
During follow-up, until progression. |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are PFS at 6 months (according to RECIST 1.1) and PFS according to irRC, the overall response rate, complete response rate, overall survival and safety. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 6 months of FU and after 5 years of follow-up |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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) | 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 | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |