| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Tumors harboring BRAF alterations
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Tumors harboring BRAF alterations |
|
| 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 | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075648 |
| E.1.2 | Term | BRAF gene mutation |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075676 |
| E.1.2 | Term | BRAF V600E mutation positive |
| E.1.2 | System Organ Class | 10022891 - Investigations |
|
| 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 master protocol is to enable the conduct of the subprotocols. The efficacy, safety, pharmacokinetics, and pharmacodynamics of Plixorafenib (FORE8394) in defined subgroups of participants with tumors harboring BRAF alterations will be evaluated in participants enrolled to each subprotocol.
Subprotocol A: To evaluate the efficacy of Plixorafenib (FORE8394) in participants with locally advanced or metastatic solid tumors or recurrent or progressive primary CNS tumors harboring BRAF fusions
Subprotocol B: To evaluate the efficacy of Plixorafenib (FORE8394) in participants with recurrent HGG harboring BRAF V600E mutation |
|
| E.2.2 | Secondary objectives of the trial |
To assess additional measures of clinical benefit
To further characterize the safety and tolerability of Plixorafenib (FORE8394)
To characterize the plasma pharmacokinetic profile of Plixorafenib (FORE8394)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female, ≥10 years of age, and weighing ≥30 kg.
a. In South Korea, individuals under the age of 19 years old are not
eligible.
b. In Sweden, individuals under the age of 18 years old are not eligible.
2. Performance status
a. ≥16 years of age: Karnofsky Performance Status (KPS) ≥60
b. <16 years of age: Lansky Performance Score ≥60.
3. All adverse events related to prior therapies (chemotherapy; radiotherapy; surgery) must have resolved to Grade 1
4. Adequate organ and marrow function within 14 days of the first dose of Plixorafenib (FORE8394)/ cobicistat
5. Female participants may be enrolled if they are:
a. Documented to be premenarchal, surgically sterile or postmenopausal OR Practicing true abstinence OR Using contraception, including 1 highly effective method, such as adequate hormonal method (eg, combined estrogen and progesterone or progesterone only containing implants, injectables, transdermal or intravaginal contraceptives) or nonhormonal methods (eg, intrauterine device in combination with a barrier contraception, from start of plixorafenib administration until 30 days after the last Plixorafenib (FORE8394) administration, and having a negative serum or urine beta subunit human gonadotropin (β-hCG) pregnancy test at screening and before initiating treatment on Day 1.
6. Male participants with female partners of childbearing potential may be enrolled if they are
a. Documented to be surgically sterile (vasectomy), OR
b. Practicing true abstinence until 30 days after the last Plixorafenib (FORE8394) administration, OR
c. Using a condom during sexual activity from start of plixorafenib
dosinguntil 30 days after the last Plixorafenib (FORE8394) administration.
7. Ability to swallow and retain orally administered medications, including a liquid suspension.
Subprotocol A specific inclusion criteria:
1. Histologic diagnosis of a solid tumor or primary CNS tumor.
2. Documentation of BRAF gene fusion in tumor and/or blood detected by an analytically validated test by DNA sequencing or RNA (transcriptome) sequencing.
3. Have an archival tissue sample available with sufficient tumor for central NGS testing and biomarker analyses.
4. Consent to provide scan(s) prior to baseline to assess change in tumor trajectory.
5. Received at least available standard therapy, is intolerant to available therapies, or the investigator has determined that treatment with standard therapy is not appropriate.
6) For Tumor-Specific Inclusion Criteria please refer to subprotocol A
Subprotocol B specific inclusion criteria:
1. Histological diagnosis of a primary CNS tumor, including but not limited to the following:
a. Adults (≥18 years) with grade 1 to 4 glioma or glioneuronal tumor (including glioblastoma, anaplastic astrocytoma, gliosarcoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, not otherwise specified [NOS], or high grade ganglioglioma), or
b. Pediatric patients (10-17 years of age) with a Grade 3 or 4 glioma or
glioneuronal tumor, including those with prior, histologically confirmed, diagnosis of a low grade glioma glioneuronal tumor and now have radiographic or histopathological findings consistent with WHO[2021]
c. Participants must have unresectable, locally advanced or metastatic disease
2. Have received at least one line of prior therapy including radiation.
3. Documented BRAF V600E mutation in tumor and/or blood detected by an analytically validated test by NGS or polymerase chain reaction (PCR) methods.
4. An archival tissue sample at less than 24 months from date of screening available with sufficient tumor for central NGS testing* and
biomarker analyses, or >24 months if the participant has never received a targeted therapy, or fresh biopsy is required if the archival sample is not available for retrospective confirmation test.
5. Measurable disease based upon RANO HGG as determined by the radiographic BICR.
6. Elapsed time from the last dose of prior therapies until the first dose of Plixorafenib (FORE8394) must meet the following criteria:
a) Systemic anticancer therapies, including cytotoxic chemotherapy, targeted therapy, antibodies, and investigational agents: 21 days or 5 half-lives (whichever is shorter)
b) Bevacizumab (Avastin): 6 weeks
c) Radiation therapy: 3 months (> 3 months needed to prevent participants with pseudo-progression from radiotherapy from being enrolled in the study). Participants may be ≥2 weeks from radiotherapy if a new lesion relative to the pre-radiation MRI develops outside the primary radiation field
d) Optune device: 24 hours.
6. Participants who are receiving corticosteroid treatment must be on a stable or decreasing dose of ≤8 mg/day of dexamethasone or equivalent corticosteroid treatment for 7 days prior to first dose of study treatments.
For complete inclusion criteria please refer to protocol |
|
| E.4 | Principal exclusion criteria |
Subprotocol A:
1) Participants with known co-occurring NF1 alteration and/or RAS-related mutations.
2) Participants with evidence of sub-clonal mutations or heterogeneity that are indicative of a prior treatment effect instead of a driver mutation.
3) Prior treatment with RAF/BRAF inhibitors active for Class 2 BRAF alterations for advanced unresectable or metastatic disease.
4) Prior treatment with a MEK inhibitor.
5) Malignancy with co-occurring activating RAS mutation(s) at any time.
6) Uncontrolled intercurrent illness that would limit compliance with study requirements.
7) Known hypersensitivity to cobicistat or its excipients.
8) Active infection requiring systemic therapy.
9) Current or planned participation in a study of an investigational agent or device.
10) Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Plixorafenib (FORE8394) or cobicistat.
11) Current active liver disease from any cause, including a positive screening test for hepatitis A virus, hepatitis B virus, or hepatitis C virus
12) Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to
prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
13) Clinically relevant cardiovascular disease
14) Are currently receiving (within 7 days of Cycle 1 Day 1) or are planning to receive during participation in this subprotocol:
a. Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat).
b. Agents that are contraindicated with cobicistat.
15) Active prior or concurrent malignancy.
16) Major surgical procedure within 14 days of the first dose of Plixorafenib (FORE8394)/cobicistat.
17) Participant is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
18) Women who are pregnant or breastfeeding.
19) Participant has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator’s opinion, may affect the safety of the participant or impair the assessment of study results.
20) For Tumor-Specific Exclusion Criteria please refer to subprotocol A
Subprotocol B:
1) Prior treatment with BRAF, ERK, and/or MEK inhibitor(s).
2) Known or suspected neurofibromatosis-1 (NF-1) and/or Ras related gene alterations.
3) Uncontrolled intercurrent illness that would limit compliance with study requirements.
4) Known hypersensitivity to cobicistat or its excipients.
5) Active infection requiring systemic therapy.
6) Current or planned participation in a study of an investigational agent or device.
7) Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Plixorafenib (FORE8394) or cobicistat (such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
8) Current active liver disease from any cause, including a positive screening test for hepatitis A virus, hepatitis B virus, or hepatitis C virus
9) Grade ≥ 2 changes in AST, ALT, gamma-glutamyl transaminase (GGT), or bilirubin attributed to
prior immune checkpoint inhibitor treatment are exclusionary, even if resolved.
10) Clinically relevant cardiovascular disease
11) Participant has leptomeningeal disease or requires increasing doses of corticosteroids to control the
CNS disease.
12) Are currently receiving or are planning to receive during participation in this subprotocol:
a) Agents that are known strong inducers or inhibitors of CYP3A4 (other than cobicistat).
b) Agents that are contraindicated with cobicistat (master protocol Appendix 7, Section 4).
13) Radiotherapy is not permitted within 3 months prior to enrollment.
14) Active prior or concurrent malignancy.
15) Major surgical procedure within 14 days of the first dose of Plixorafenib (FORE8394)/cobicistat.
16) Participant is unwilling or unable to comply with scheduled visits, drug administration plan,
laboratory tests, or other study procedures and study restrictions.
17) Women who are pregnant or breastfeeding.
18) Participant has a prior or ongoing clinically significant illness, medical condition, surgical history,
physical finding, or laboratory abnormality that, in the investigator’s opinion, may affect the safety of the participant or impair the assessment of study results.
19) Progressively worsening in frequency or severity seizures indicative of rapid tumor progression, or seizures poorly controlled with available therapy
For complete exclusion criteria please refer to protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint for Subprotocol A:
- ORR as determined by RECIST v1.1 or RANO criteria for HGG, LGG, or brain metastases as appropriate by tumor type, by BICR
Primary Endpoint for Subprotocol B:
- ORR as determined by RANO HGG or LGG criteria (as appropriate) by BICR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks (±5 days) after Cycle 1 Day 1, regardless of treatment delays or interruptions, until 48 weeks after Cycle 1 Day 1. After 48 weeks, the frequency of scans can be decreased to every 8 weeks (±7 days) until 96 weeks after Cycle 1 Day 1, and then every 12 weeks (±14 days) thereafter. |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoint for Subprotocol A:
-DOR as determined by RECIST v1.1 or RANO per BICR
DOR estimates will be presented as supplements to the primary ORR analysis, via Kaplan-Meier analysis based on all responders (CR + PR for solid tumors and HGG, CR, PR, + MR for LGG)
-ORR as determined by RECIST v1.1 or RANO per investigator assessment
-DOR as determined by RECIST v1.1 or RANO per investigator assessment
- CNS-DOR by BICR (participants with solid tumors and CNS metastasis at baseline, and reported based upon time from prior radiation therapy)
-Landmark DOR: % of responders with DOR at 6 month, 12 month, and 18-month landmarks
-Time to Response by BICR
-PFS by BICR
-PFS by investigator’s assessment
-Percentage of participants with PFS (PFS rate) at 6 month, 12 month, and 18-month landmarks, by RECIST v1.1 or RANO by BICR and by investigator assessment
-OS
-DCR, defined as CR, PR, or SD for solid tumor and HGG; CR, PR, MR or SD for LGG
-CNS-ORR by BICR (participants with solid tumors and who have CNS metastasis at baseline, and reported based upon time from prior radiation therapy
-Adverse events
-Physical examinations
-Vital signs
-12-lead electrocardiograms
-Clinical laboratory tests (hematology, clinical chemistry, coagulation)
-Plasma concentrations of Plixorafenib (FORE8394) and metabolite(s)
- For participants with primary CNS tumor, changes in seizure
assessments including frequency and severity of seizures, over time will be assessed to characterize additional efficacy parameters for the natural history of disease
Secondary Endpoint for Subprotocol B:
-DOR as determined by RANO HGG or LGG criteria per BICR
DOR estimates will be presented as supplements to the primary ORR analysis, via Kaplan-Meier analysis based on all responders (CR + PR + MR)
-ORR as determined by RANO HGG or LGG criteria per investigator assessment
-DOR as determined by RANO HGG or LGG criteria per investigator assessment
-Landmark DOR: % of responders with DOR at 6 month, 12 month, and 18-month landmarks
-Time to Response by BICR
-PFS by BICR
-PFS by investigator’s assessment
-Percentage of participants with PFS (PFS rate) at 6 month, 12 month, and 18-month landmarks, by RANO HGG or LGG criteria by BICR and by investigator assessment
-OS
-DCR, defined as proportion of participants with CR, PR, or SD
Subgroup analyses of low grade (including Grade 1 and 2) and high
grade (including Grade 3 and 4) primary CNS tumors will be reported
-Adverse events
-Physical examinations
-Vital signs
-12-lead electrocardiograms
-Clinical laboratory tests (hematology, clinical chemistry, coagulation)
-Plasma concentrations of Plixorafenib (FORE8394) and metabolites
-Changes in seizure assessments including frequency and severity of
seizures, over time will be assessed to characterize additional efficacy
parameters for the natural history of disease |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Clinical benefit: Every 6 weeks (±5 days) after Cycle 1 Day 1, regardless of treatment delays or interruptions, until 48 weeks after Cycle 1 Day 1. After 48 weeks, the frequency of scans can be decreased to every 8 weeks (±7 days) until 96 weeks after Cycle 1 Day 1, and then every 12 weeks (±14 days) thereafter.
Safety: at every study visit
PK: Days 1 and 15 of Cycle 1 and on day 1 of every other Cycle, starting with Cycle 3. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | No |
| 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.8.3 |
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.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| Korea, Republic of |
| United Kingdom |
| United States |
| France |
| Germany |
| Italy |
| Spain |
| Sweden |
|
| 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 end of the study is defined as the date of the last visit or last procedure of the last participant in all subprotocols, including poststudy follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 10 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 12 |
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