| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| 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 |
PHASE 1:
1) Arm A:
• To assess safety and tolerability of BGB-290 combined with RT
• To identify dose-limiting toxicity (DLT) and determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) for BGB-290 combined with RT
• To select the recommended Phase 2 schedule for full-dose BGB 290 combined with RT
2) Arm B:
• To assess safety and tolerability of BGB-290 combined with RT and TMZ
• To identify DLTs and determine the MTD or MAD for TMZ combined with RT and the MTD/MAD for BGB-290 of Arm A
• To select the RP2D for TMZ combined with RT and the MTD/MAD for BGB-290 of Arm A
3) Arm C:
• To assess safety and tolerability of BGB-290 combined with TMZ
• To identify DLTs and determine the MTD or MAD for TMZ combined with full-dose BGB-290
• To select the RP2D for TMZ combined with full-dose BGB 290
PHASE 2:
To assess the efficacy of BGB-290 combined with:
1) RT (Arm A)
2) RT and TMZ (Arm B)
3) TMZ (Arm C) |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b, all Arms
• To characterize the PK of BGB-290 in combination with RT and/or TMZ
• To make a preliminary assessment of BGB-290 efficacy in combination with RT and/or TMZ
Phase 2, all Arms
• To assess safety and tolerability of BGB-290 in combination with RT and/or TMZ
• To characterize the PK of BGB-290 in combination with RT and/or TMZ |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
ALL PATIENTS
1 Age ≥ 18 years old.
2 Confirmed diagnosis of glioblastoma (WHO Grade IV).
3 Ability to undergo serial MRIs.
4 ECOG status ≤ 1.
5 Adequate bone marrow function.
6 Adequate renal and hepatic function.
7 Ability to swallow whole capsules.
Subjects in Arms A and B (not Arm C) must also meet inclusion criteria:
8 No previous treatment for GB except surgery.
9 Able to start radiation therapy ≤ 49 days after surgery but ≥ 14 days
after a biopsy or ≥28 days after an open biopsy or craniotomy with
adequate wound healing.
10 Documented unmethylated MGMT promoter status.
Subjects in Arm C ESCALATION only must also meet inclusion criteria:
11 Documentation of MGMT promoter status
It is preferable to determine MGMT status by MS-PCR. Other
acceptable platforms include pyrosequencing methodologies and MSHRM
assays with comparable sensitivity, applied to archival or fresh
tumor tissue.
12 No prior systemic chemotherapy other than TMZ for GB and nd no
prior anti-angiogenic therapy
13 Histologically confirmed secondary glioblastoma
14 Progressive disease > 2 months after completion of first line therapy.
15 Disease that is evaluable or measurable by mRANO
Subjects in Arm C EXPANSION only must also meet inclusion criteria:
16 Histologically confirmed de novo (primary) glioblastoma with
unequivocal first
progressive disease (PD) after RT with concurrent/adjuvant TMZ
chemotherapy as defined
by one or more of the following:
PD ≥ 3 months after the end of radiotherapy
PD that is clearly outside the radiation field
PD that has been unequivocally proven by surgery/biopsy
17 Disease that is measurable as defined by RANO criteria
18 Documentation of MGMT promoter status.
For full list of inclusion criteria refer to the study protocol. |
|
| E.4 | Principal exclusion criteria |
ALL PATIENTS:
1. Chemotherapy, biologic therapy, immunotherapy, or investigational
agent ≤ 21 days (or ≤ 5 half-lives, whichever is shorter) prior to Day 1
2. Unresolved acute effects of any prior therapy of Grade ≥ 2, except for
AEs not constituting a safety
risk by investigator judgement
3. Major surgical procedure, open biopsy, or significant traumatic injury
≤ 28 days prior to Day 1, or anticipation of need for major surgical
procedure during the course of the study.
4. Other diagnosis of malignancy
- Except for surgically excised non-melanoma skin cancer, adequately
treated carcinoma in situ of the cervix, localized prostate cancer treated
with curative intent, adequately treated low-stage bladder cancer, ductal
carcinoma in situ treated surgically with curative intent, or a malignancy
diagnosed >2 years ago with no current evidence of disease and no
therapy ≤ 2 years prior to Day 1
5. Active infection requiring systemic treatment
6. Active cardiac disease, inflammatory gastrointestinal disease,
bleeding disorder (for details see protocol)
7. Anticoagulation with heparin, warfarin, or other anticoagulants (for
details see protocol)
8. Use ≤ 10 days (or ≤ 5 half-lives, whichever is shorter) prior to Day 1
or anticipated need for food or
drugs known to be strong or moderate CYP3A inhibitors or strong CYP3A
inducers including known enzyme inducing anti-epileptic drugs
FOR PATIENTS IN Arm B and C (NOT applicable to Arm A)
9. Known hypersensitivity to any temozolomide component or to
dacarbazine (DTIC)
10. Have hereditary problems of galactose intolerance, the Lapp lactase
deficiency, or
glucose-galactose malabsorption
For full list of exclusion criteria see protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b, all Arms
1) Incidence and nature of DLTs
2) Incidence, nature, and severity of AEs, graded according to the NCI-CTCAE, v4.03
3) Number of cycles (Arm C only) and the dose intensity of each component of the treatment regimens, and changes in vital signs and clinical laboratory test results during and following study treatment
Phase 2, Arm A and B
4) Modified disease control rate (DCR) as assessed using the modified Response Assessment in Neuro-Oncology (mRANO), version 1.1
Phase 2, Arm C
5) Objective response rate (ORR) as assessed using mRANO |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1,2,3: During weekly visits
4,5: within 14 days prior to Day 1 and then approximately 4 weeks after completion of RT as part of the EOT visit. Subjects without progressive disease at the EOT visit every 8 weeks (± 7 days) during the Follow-up Phase. |
|
| E.5.2 | Secondary end point(s) |
Phase 1b, all Arms
1) PK parameter for pamiparib of steady-state Ctrough
2) Modified DCR (Arms A and B), DCR (Arm C), ORR and clinical benefit rate (CBR)
3) Time-to-event endpoints: e.g., duration of response (DOR), progression-free survival (PFS) and overall survival (OS)
Phase 2, Arm A and B
4) ORR and CBR as assessed using RANO criteria
5) Time-to-event endpoints: e.g., DOR, PFS and OS
6) Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03
7) The dose intensity of each component of the treatment regimens, and changes in vital signs and clinical laboratory test results during and following study treatment
8) PK parameter for pamiparib
Phase 2, Arm C
9) DCR and CBR as assessed using RANO criteria
10) Time-to-event endpoints: e.g., DOR, PFS and OS
11) Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03
12) Number of cycles and the dose intensity of each component of the treatment regimens, and changes in vital signs and clinical laboratory test results during and following study treatment
13) PK parameter for pamiparib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1,8, 13: Day 1, 15, EOT (Arm A), Day 1, 15 (Arm B, C)
2,3,4,5,9,10: Within 14 days prior to Day 1 and EOT. Subjects without progressive disease at the EOT visit must then be followed with MRIs every 8 weeks (± 7 days) during the Follow-up Phase.
6,7,11,12: weekly during study visits
|
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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.8.3 |
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 | 15 |
| 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 |
| Australia |
| European Union |
| Switzerland |
| United States |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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