Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Defactinib · 8 trials · 14 indications
Defined as the days from the date of standard of care (SOC) chemotherapy treatment start to progression or death.
* PFS is defined as the duration of time from start of standard of care chemotherapy treatment to time of progression or death, whichever occurs first. The alive patients without progression will be censored at the last follow-up. * Progressive disease: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
* The recommended phase II dose will be determined from the maximum tolerated dose (MTD) found in the dose escalation cohort. * The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle (21 days). Dose escalations will proceed until the MTD has been reached or the completion of cycle 5.
For Cohort A, the primary objective will be to evaluate preliminary response rate of defactinib and avutometinib in patients with RAS mutant, BRAF mutant, NF1 mutant, and triple RAS/BRAF/NF1 wild type (wt) melanoma (includes RAF fusions). Measurable target lesions to be defined as all untreated and measurable (≥ 0.5 cm by 2 dimensional diameter measurements) present at the time of enrollment on study.
For Cohort B, a Phase 1 run-in will be performed with the primary objective of evaluating the safety and tolerability of the combination of defactinib, avutometinib, and encorafenib in patients with BRAF V600E/K mutant melanoma with at least one untreated brain metastasis.
A composite by dose level to include incidence of AEs, SAEs, dose interruptions and dose reductions as a measure of safety and tolerability. Abnormal Clinical significant laboratory results, ECG measurements, vital signs measurement, physical examination findings, and ECOG performance status were captured as adverse events. The severity of AEs were evaluated according to CTCAE (Common Toxicity Criteria for Adverse Effects) 4.03
Adverse events and their frequency, duration and severity, as determined based on CTCAE 4.03
The RP2D will be determined based on the maximum tolerated dose (MTD) of defactinib (VS-6063) in combination with paclitaxel as determined by number of participants with dose limiting toxicities (DLTs) related to defactinib in combination with paclitaxel
| Arm | Type | Description |
|---|---|---|
| Experimental Arm: SBRT + Defactinib + Avutometinib | EXPERIMENTAL | Participants will receive approximately 12 months of treatment on study with 5 fractions of adaptive SBRT with 12 cycles of oral defactinib + avutometinib beginning on Day 2 of radiation. Cycles are 28 days in length. Defactinib is dosed twice a day and avutometinib is dosed twice a week (e.g. Monday and Thursday, Tuesday and Friday, etc.) on a 3 weeks on, 1 week off schedule. The first 6 participants will be enrolled in the Safety Lead-In cohort to monitor for dose-limiting toxicities. Patients who are candidates for surgical resection will undergo standard of care surgery at 2 weeks post-end of SBRT (+/- 1 weeks) or 12 weeks post-end of SBRT (+/- 2 weeks). These patients will discontinue defactinib and avutometinib the day prior to the operation and will resume taking it 4 to 6 weeks after surgery for the remainder of the 12 cycles. Patients who are not candidates for surgical resection will continue to receive defactinib plus avutometinib uninterrupted. |
| Control Arm: SBRT | ACTIVE_COMPARATOR | Participants will receive 5 fractions of adaptive SBRT. |
| Adaptive SBRT + Defactinib | EXPERIMENTAL | * Participants in this study will receive 5 fractions of magnetic resonance adaptive stereotactic body radiation therapy (SBRT) and seventeen 21-day cycles of defactinib (beginning on Day 2 of radiation). * Participants who are candidates for surgical resection will undergo standard of care surgery at 2 weeks post-end of SBRT (+/- 1 weeks) or 12 weeks post-end of SBRT (+/- 1 week). These participants will discontinue defactinib the day prior to the operation and will resume taking it for the remainder of the 17 cycles 4 to 6 weeks after surgery. Participants who are not candidates for surgical resection will continue to receive defactinib uninterrupted. All participants should receive 17 cycles of defactinib unless they experience disease progression or intolerable toxicity. |
| Adaptive SBRT | ACTIVE_COMPARATOR | -Participants in this study will receive 5 fractions of magnetic resonance adaptive stereotactic body radiation therapy (SBRT) |
| VS-6063 (defactinib) | EXPERIMENTAL | Administered orally BID in a 21 day cycle |
| Dose escalation (defactinib, pembrolizumab, gemcitabine) | EXPERIMENTAL | * Defactinib is an oral drug which will be administered on an outpatient basis at the prescribed dose twice a day daily during each 21-day cycle. * Pembrolizumab is an intravenous (IV) drug which will be administered on an outpatient basis over 30 minutes (-5/+10) at a dose of 200 mg on Day 1 of each 21-day cycle. * Gemcitabine is an IV drug which will be administered on an outpatient basis over 30 minutes at the prescribed dose on Days 1 and 8 of each 21-day cycle. * Participants enrolled in Dose Level 1 and 2 will not receive gemcitabine. |
| Dose expansion (defactinib, pembrolizumab, gemcitabine) | EXPERIMENTAL | * Defactinib is an oral drug which will be administered on an outpatient basis at the prescribed dose twice a day daily during each 21-day cycle. * Pembrolizumab is an intravenous (IV) drug which will be administered on an outpatient basis over 30 minutes (-5/+10) at a dose of 200 mg on Day 1 of each 21-day cycle. * Gemcitabine is an IV drug which will be administered on an outpatient basis over 30 minutes at the prescribed dose on Days 1 and 8 of each 21-day cycle. * Participants enrolled in Dose Level 1 and 2 will not receive gemcitabine. |
| Phase II, Defactinib and Avutometinib (Cohort A) | EXPERIMENTAL | Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. |
| Phase Ib, Defactinib, Avutometinib, and Encorafenib (Cohort B) | EXPERIMENTAL | Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Encorafenib will be administered orally to a small cohort to a limited dose finding cohort using a Bayesian optimal interval (BOIN) design to evaluate safety, toxicity, and recommended phase II dose for dosage of encorafenib when combined with avutometinib and defactinib. Dose escalation/de-escalation levels for Encorafenib: Dose Level -1: 225 mg Daily (three 75mg capsules) Dose Level 0: 300 mg Daily (four 75mg capsules) Dose Level 1: 450 mg Daily (six 75mg capsules) |
| Phase II, Defactinib, Avutometinib, and Encorafenib (Cohort B) | EXPERIMENTAL | Avutometinib will be administered at 3.2 mg biweekly orally (e.g., Monday/Thursday, Tuesday/Friday, or Wednesday/Saturday) for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Defactinib will be administered at 200 mg twice a day orally for 3 weeks, followed by a 1-week rest period, in each 4-week (28-day) cycle. Encorafinib will be administered orally at doses defined in the dose finding portion (225mg - 450mg) Daily continuously (days 1-28 of a 28 day cycle) for Cohort B. |
| Defactinib treatment | EXPERIMENTAL | Single dose of 400 mg \[14C\]-defactinib, oral suspension |
| Defactinib | EXPERIMENTAL | Oral defactinib (VS-6063) administered twice a day (BID) during a 21 day cycle. |
| defactinib (VS-6063) plus paclitaxel | EXPERIMENTAL | Oral defactinib (VS-6063) administered twice daily, in combination with intravenous paclitaxel administered on Days 1, 8, and 15 of a 28 day cycle. |
| Name | Type | Description |
|---|---|---|
| Stereotactic body radiotherapy | RADIATION | MRIdian and Ethos (adaptive radiation platforms) |
| Defactinib | DRUG | Taken with 30 minutes of a meal |
| Avutometinib | DRUG | Can be taken without regard to food. |
| Adaptive stereotactic body radiation therapy | DEVICE | * Will be administered using MRIdian and Ethos * 50 Gy in 5 fractions |
| Tumor biopsy | PROCEDURE | -Baseline and 12-14 weeks after end of SBRT (or at time of surgery) |
| Research blood draw | PROCEDURE | -Baseline, 6-8 weeks after the end of SBRT, and 12-14 weeks after the end of SBRT |
| defactinib (VS-6063) | DRUG | - |
| Pembrolizumab | BIOLOGICAL | - |
| Gemcitabine | DRUG | - |
| Encorafenib | DRUG | Encorafinib administered orally per arm description. |
| Paclitaxel | DRUG | - |
Inclusion Criteria: * Histologically or cytologically confirmed advanced pancreatic adenocarcinoma that is considered borderline resectable or locally advanced per institutional standardized criteria of unresectability or medical inoperability (NCCN guidelines 2.2021 PANC-C 1 of 2). * Patients with...