| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with locally advanced, unresectable or metastatic BRAFV600 mutant melanoma. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with locally advanced, unresectable or metastatic melanoma with a BRAFV600 mutation |
|
| 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 | 10025650 |
| E.1.2 | Term | Malignant melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025667 |
| E.1.2 | Term | Malignant melanoma site/stage unspecified |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10027480 |
| E.1.2 | Term | Metastatic malignant melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
The objective of the study is to assess if an early switch (i.e. switch at 3 months) from targeting the Ras/Raf signalling pathway by BRAF and MEK inhibition to immunologic checkpoint inhibition with an anti-PD-L1 antibody leads to prolongation of progressionfree and overall survival outcomes in patients with unresectable or metastatic BRAFV600 mutant melanoma. Furthermore, the safety of the study treatment will be assessed. The following endpoints will help to address the study objectives:
Primary endpoint:
PFS1 defined as time from start of run-in phase (date of first intake of study drug) to first documented tumor progression date according to RECIST v. 1.1 (PD1) or death by any cause, whichever occurs first (Figure 2). PFS1 will be based on the disease assessment or date of death provided by the local investigator. For patients who remain alive and whose disease has not progressed, PFS1 will be censored on the date of last visit/contact when a disease assessment was performed. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary endpoints:
• Time to Second Objective Disease Progression (PFS2)
• Safety
• Overall Survival (OS) of patients defined as the time from start of run-in phase until documented date of death, for any cause. Patients still alive will be censored at the time of last visit/contact.
• Overall survival rate at 12 months, 24 months, 36 months, and 48 months defined as the rate of patients alive 12 months, 24 months, 36 months, and 48 months, respectively after start of run-in phase
• 12-months and 24-months disease control rate (DCR), best overall objective response rate (OORR), time to overall objective response (OOR) and duration of OOR.
• Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status or multiple
and/or symptomatic brain metastasis and/or leptomeningeal disease
o From vemurafenib + cobimetinib to atezolizumab (Arm A)
o From atezolizumab to vemurafenib + cobimetinib (Arm B)
• PFS3 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The translational research program will focus on the discovery of biomarkers for improvement of melanoma therapy, and to evaluate the biologic effects of treatment sequence on the molecular profile and biomarker expression in tissue and plasma. Therefore tumor tissue and blood samples, respectively will be analyzed to assess the relationship of the tumor immune and signaling biomarker landscape and efficacy, to evaluate non-inherited genetic alterations of circulating free tumor-specific DNA in plasma and to assess and monitor the immunophenotype in peripheral blood mononuclear cells.
The patient questionnaires will focus on the medication adherence of the patients. Paper-based as well as electronic documentation will be available. The patients can choose between both. Since the use of electronic systems for self-reported medication adherence is a new approach in melanoma research, the aim of this approach is to analyze both the patient group that opts for Alcedis eMARS as well as the patient group that opts for the paper-based documentation. Reasons for not participating in the Alcedis eMARS program will be documented. Furthermore the user-friendliness, practicality, and user satisfaction of Alcedis eMARS will be assessed by patient and investigator questionnaires. In addition the quality of life of the patients will be assessed. To address these objectives, standardized and study-specific patient questionnaires will be used. To analyze the investigator´s satisfaction with Alcedis eMARS, the investigator has to fill in specific questionnaires on different timepoints. Additionally, the self-reported medication adherence will be analyzed in both patient groups (patients using Alcedis eMARS or using the paper-based documentation) also taking the results of the pill-count done by the study centers into account. |
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| E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent for the trial.
2. Male or female patient being >= 18 years of age on day of signing informed consent.
3. Histologically confirmed diagnosis of locally advanced, unresectable or metastatic melanoma AJCC 7th edition (unresectable stage IIIB, IIIC, IVM1a, IVM1b, or IVM1c) without active or untreated brain metastases; all known CNS lesions must have been treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND the patient must be without evidence of clinical or radiographic disease progression in the CNS for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms must have returned to baseline, the patient must have no evidence of new or enlarging brain metastases, and the patient must not have used steroids in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks prior to trial treatment .
4. No previous therapy for the advanced or metastatic stage. Prior adjuvant therapy is permitted (e.g. IFN, IL-2-therapy, chemo- or radiotherapy). Prior adjuvant therapy has to be terminated (last dose) at least 28 days before enrollment. Patients who are in follow-up period of a clinical trial in adjuvant setting and progressing may be enrolled / randomized.
5. Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion.
6. Presence of BRAF mutation (V600) in tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion prior to enrollment.
7. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
9. Demonstrate adequate organ function as defined as following. All screening labs should be performed within 28 days of treatment initiation.
9.1 Hematological:
• Absolute neutrophil count ≥1,500 /mcL
• Platelets ≥100,000 / mcL
• Hemoglobin ≥9 g/dL OR ≥5.6 mmol/L
• INR and aPTT < 1.5 x ULN
9.2 Renal:
• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥50 mL/min for subject with creatinine levels > 1.5 X institutional ULN
9.3 Hepatic:
• Serum total bilirubin ≤ 1.5 X ULN
• AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases
10. Adequate cardiac function:
• Left ventricular ejection fraction (LVEF) ≥ 50% as determined by multigated acquisition (MUGA) scan or echocardiogram
• QTc interval ≤ 450 ms
11. All prior treatment-related toxicities (except alopecia) following adjuvant therapy must be ≤ Grade 1 according tothe CTCAE (version 4.03) at the time of: randomization.
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
12. Able to take oral medications.
13. Patient is deemed by the investigator to have the initiative and means to be compliant with the protocol.
14. Female subject of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
15. Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective forms of contraception according to CTFG during the course of this study and for at least 6 months after completion of study therapy. Birth control methods which may be considered as highly effective can achieve a failure rate of less than 1% per year when used consistently and correctly.
- Females of childbearing potential are defined as sexually mature women without prior oophorectomy or hysterectomy who have had menses within the last 12 months.
- Females are not considered to be of childbearing potential if amenorrheic for > 12 months and follicle-stimulating hormone (FSH) levels ≥ 40 IU/L.
- For females who have been amenorrheic for ≥ 2 years, the requirement for FSH measurement at screening will be waived.
- Highly effective forms of contraception include hormonal contraception (combined or progesterone-only) associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomy (must have received medical assessment of the surgical process) and sexual abstinence (complete avoidance of heterosexual intercourse), according to the CTFGs “Recommendations related to contraception and pregnancy testing in clinical trials”. Please note that potential interactions between vemurafenib and hormonal contraceptives may decrease the effectiveness of hormonal contraceptives.
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|
| E.4 | Principal exclusion criteria |
1.Use of any investigational or non-registered product within the 30 days before registration.
2.Diagnosis of immunodeficiency or receiving systemic steroid therapy in dosing exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
3.Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) also in an adjuvant setting.
4.Prior therapy with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib and/or MEK inhibitor (including but not limited to trametinib, AZD6244, Binimetinib, Cobimetinib) also in an adjuvant setting.
5.Prior major surgery.
6.Known additional malignancy that is progressing or requires active treatment within 3 years prior to the study. Exceptions include adequately treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy without evidence or recurrence.
7.Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Note: Subjects with previously treated brain metastases may participate provided they are stable, have no evidence of new or enlarging brain metastases, and are not using steroids for at least 3 weeks prior to trial treatment.
8.History of leptomeningeal metastases
9.History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO) or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).
10.History of retinal degenerative disease.
11.History of allogenic bone marrow transplantation or organ transplantation.
12.History of Gilbert’s syndrome
13.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
•History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior to screening.
•Symptomatic chronic heart failure, history or current evidence of clinically significant cardiac arrhythmia and / or conduction abnormality < 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia.
•History of congenital long QT syndrome or mean (average of triplicate measurements) QTc measured using Fridericia’s method > 450 ms at baseline or uncorrectable abnormalities in serum electrolytes.
14.Uncontrolled arterial hypertension despite medical treatment.
15.Patients who have neuromuscular disorders which are associated with elevated CK (e. g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
16.Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel resection).
17.Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids in dosing exceeding 10 mg daily of prednisone equivalent or immunosuppressive agents. Note: Subjects with vitiligo or controlled asthma/atopy would be an exception to this rule.
Note: Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. /Note: Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome will not be excluded from the study.
18.Evidence of interstitial lung disease or active, non-infectious pneumonitis.
19.Active infection requiring systemic therapy.
20.Pregnancy/breastfeeding/expecting to conceive or father children within the duration of the trial, starting with pre-screening or screening visit through at least 6 month after the last dose of trial treatment.
21.Positive test for HIV (HIV 1/2 antibodies).
22.Positive test for Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
23.Known hypersensitivity reaction to any of the components of study treatment.
24.Medical, psychiatric, cognitive or other conditions, including known alcohol or drug abuse that would not permit the subject to complete the study or sign informed consent.
25.Patients taking non-topical medication known to be a strong inhibitor of CYP3A4. However, patients who either discontinue their treatment or switch to another medication at least three days prior to registration / randomization are eligible.
26.Patients having received a live, attenuated vaccine within 4 weeks prior to the first dose of trial treatment.
27.Legal incapacity or limited legal capacity.
28.Presence of uveal melanoma |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS1 defined as time from start of run-in phase (date of first intake of study drug) to first documented tumor progression date according to RECIST v. 1.1 (PD1) or death by any cause, whichever occurs first (Figure 2). PFS1 will be based on the disease assessment or date of death provided by the local investigator. For patients who remain alive and whose disease has not progressed, PFS1 will be censored on the date of last visit/contact when a disease assessment was performed. |
|
| E.5.2 | Secondary end point(s) |
• PFS2
• Safety
• Overall Survival (OS) of patients
• Overall survival rate
• 12-months and 24-months disease control rate (DCR), best overall objective response rate (OORR), time to overall objective response (OOR) and duration of OOR.
•Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status or multiple
and/or symptomatic brain metastasis and/or leptomeningeal disease
o From vemurafenib + cobimetinib to atezolizumab (Arm A)
o From atezolizumab to vemurafenib + cobimetinib (Arm B)
• PFS3 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS2: from start of run-in phase to 2nd disease progression according to RECIST v. 1.1 (PD2) following randomization or death by any cause
- Safety: during the whole study
- OS: from start of run-in phase until date of death
- OS rate at 12, 24, 36 and 48 months
- 12-months and 24-months disease control rate (DCR), best overall objective response rate (OORR), time to overall objective response (OOR) and duration of OOR.
- Rate of patients with progressive disease who could not cross-over to subsequent line of therapy due to deterioration of ECOG status or multiple and/or symptomatic brain metastasis and/or leptomeningeal disease: over the whole study
-PFS3:from the 1st tumorPD (PD1) until the 2nd tumor PD (PD2) after randomization or death by any cause, whichever occurs first. |
|
| 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 | 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 | 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) | No |
| 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
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 | No |
| 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 |
| France |
| Germany |
| Greece |
| Poland |
| Serbia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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