Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as defactinib (VS-6063), VS-6063, PF-04554878
Defactinib · 10 trials · 16 indications
Percent of subjects with a pathologic complete response (pCR) per the tumor regression grade scores established by the College of American Pathologist: Grade 0= complete response (no viable cancer cells), Grade 1= near complete response (single cells or rare small groups of cancer cells), Grade 2= partial response (residual tumor with evidence of regression), or Grade 3= no response (extensive residual tumor with no evidence of regression).
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.
Measured Via Adverse Events
ORR by RECIST 1.1.
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 |
|---|---|---|
| Arm A - Pembrolizumab and Defactinib | EXPERIMENTAL | - |
| Arm B - Pembrolizumab | EXPERIMENTAL | - |
| 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 (VS-6063) +Carboplatin/Paclitaxel | EXPERIMENTAL | Defactinib (VS-6063) +Carboplatin/Paclitaxel |
| 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. |
| 1 | EXPERIMENTAL | Dose escalation study with Expansion Cohorts at RP2D and Schedule |
| Name | Type | Description |
|---|---|---|
| Pembrolizumab | DRUG | Following standard of care neoadjuvant chemotherapy, subjects will receive two doses of pembrolizumab (200mg) IV 3 weeks apart prior to surgery. After surgery, subjects will receive adjuvant standard of care chemotherapy. Following adjuvant chemotherapy, subjects will receive 8 doses of pembrolizumab (200mg) IV 3 weeks apart. |
| Defactinib | DRUG | Following 2 cycles of standard of care neoadjuvant chemotherapy, subjects will receive 400 mg defactinib twice a day up until 2 days preceding their surgery (approximately 6 weeks) during the immunotherapy cycles with pembrolizumab. After surgery, subjects will receive adjuvant standard of care chemotherapy. Following adjuvant chemotherapy, subjects will receive 400mg defactinib twice a day for 24 weeks. |
| Stereotactic body radiotherapy | RADIATION | MRIdian and Ethos (adaptive radiation platforms) |
| 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 | - |
| Gemcitabine | DRUG | - |
| Encorafenib | DRUG | Encorafinib administered orally per arm description. |
| VS-6063 | DRUG | Phase 1: * First 3 patient cohort: VS-6063 200 mg PO twice daily * IF TOLERATED, Second 3 patient cohort: VS-6063 400 mg PO twice daily, Phase 2: VS-6063 400 mg PO twice daily of a 28 day cycle until disease progression or unacceptable toxicity. |
| Paclitaxel | DRUG | Phase 1: * First 3 patient cohort: paclitaxel 80 mg/m2 infused IV continuously over 1 hour on days 1, 8, and 15 of a 28 day cycle. * IF TOLERATED, Second 3 patient cohort: paclitaxel 80 mg/m2 infused IV continuously over 1 hour on days 1, 8, and 15 of a 28 day cycle. Phase 2: Paclitaxel 80 mg/m2 infused continuously over 1 hour on days 1, 8, and 15 of a 28 day cycle until disease progression or unacceptable toxicity. |
| Carboplatin | DRUG | Phase 1: * First 3 patient cohort: carboplatin (AUC of 5 mg/mL/min) IV infused continuously over 1 hour on day 1 of a 28 day cycle. * IF TOLERATED, Second 3 patient cohort: carboplatin (AUC of 5 mg/mL/min) IV infused continuously over 1 hour on day 1 of a 28 day cycle. Phase 2: carboplatin (AUC of 5 mg/mL/min) infused continuously over 1 hour on day 1 of a 28 day cycle until disease progression or unacceptable toxicity. |
| PF-04554878 | DRUG | Oral pills at increasing dose twice daily, 21 day cycle, continuous treatment schedule until progression of disease, unacceptable toxicity, or patient request. Some patients will undergo serial biopsy and/or FDG-PET imaging |
Inclusion Criteria: * Age ≥18 years. * Has pancreatic ductal adenocarcinoma * Has resectable disease at the time of diagnosis * Has not received any systemic therapy for pancreatic ductal adenocarcinoma * Has stage ≤ IIb disease at time of diagnosis and enrollment * Elevated tumor marker, CA (carbo...
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Defactinib is an investigational small molecule being studied in oncology for advanced solid tumors, including pancreatic cancer, ovarian cancer, non small cell lung cancer, cutaneous melanoma with brain metastases, and other non hematologic cancers. It is not yet approved and remains in clinical development.
Defactinib targets PTK2 and PTK2B, also known as focal adhesion kinase (FAK) and its related kinase. It acts as an inhibitor of these targets, which are involved in cell adhesion and signaling pathways that support tumor growth and survival.
Defactinib is being developed by Verastem, Inc., which trades under the ticker VSTM. The company is the sponsor of the clinical trials evaluating defactinib in various cancer indications.
Defactinib is in Phase 1 clinical development. It is an investigational agent and has not been approved by the FDA. Trials are ongoing to evaluate its safety and activity in advanced solid tumors and other cancers.
Defactinib is being studied in several clinical trials, including NCT07126158, a Phase 2 trial combining stereotactic body radiotherapy with FAK and RAF/MEK inhibition in advanced pancreatic adenocarcinoma; NCT06194929, a Phase 1 trial with avutometinib with or without encorafenib for brain metastases from cutaneous melanoma; NCT04331041, a Phase 2 trial with stereotactic body radiotherapy in advanced pancreas adenocarcinoma; and NCT03727880, a completed Phase 2 trial with pembrolizumab in resectable pancreatic ductal adenocarcinoma.
Yes, defactinib is also known as VS-6063. These names refer to the same investigational drug candidate developed by Verastem, Inc.