Phase II Trial of Vemurafenib and Sorafenib in Pancreatic Cancer

• Vemurafenib (Drug): Vemurafenib 480 mg PO BID daily given with Sorafenib 200 mg PO BID
• Sorafenib (Drug): Sorafenib 200 mg PO BID and Vemurafenib 480 mg PO BID daily

Primary outcomes

• Disease Control Rate (DCR) [Initiation of study treatment until 16 weeks.]: Disease control rate (DCR) is defined as the combination of patients with complete response + partial response + stable disease at 16 weeks, divided by the total number of patients. Response is defined using RECIST v1.1 imaging criteria.

Secondary outcomes

• Adverse Events Possibly or Definitely Related to Vemurafenib in Combination Wit Sorafenib [Initiation of study treatment up to 30 days post treatment, an average of 90 days]: The number of patients who experienced an adverse event (AE) determined to be possibly or definitely related to the study treatment of vemurafenib + sorafenib. Adverse events occurring were graded according to the NCI Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Grade refers to the severity of the AE and are given on a 1-5 scale, with each scale having unique clinical descriptions of severity for each AE based on this general guideline: * Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. * Grade 2: Moderate; minimal, local or noninvasive intervention indicated * Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling * Grade 4: Life-threatening consequences; urgent intervention indicated. * Grade 5: Death related to AE. Note: All AEs were grade 3 or lower in this study.
• Progression-free Survival (PFS) [Initiation of study treatment up to study completion, up to 2 years.]: Progression-free survival (PFS) is defined as first dose treated until the date of disease progression as measured by imaging using RECIST v1.1 criteria.
• Overall Survival (OS) [Initiation of study treatment up to study completion, up to 2 years.]: Survival was defined as the time from initiation of study treatment (C1/D1) to date of death. In the absence of confirmation of death, survival time was censored at the last date the patient was known to be alive.
• Percent Change in Plasma Levels of Phospho-ERK From Baseline [Initiation of study treatment to end of study treatment, up to 90 days.]: Phospho-ERK is a key downstream effector of the RAS/RAF/MEK signaling pathway that is proposed to be targeted by vemurafenib and sorafenib treatment. Plasma levels of phospho-ERK were measured over multiple treatment timepoints to gain molecular insight into targeted pathway suppression of the study regimen. Six patients who had blood samples available for the baseline (screen) and at least one on- or post-treatment time point were included in this analysis. Timepoints include Baseline, Cycle 2 Day 1 (C2D1), Cycle 3 Day 1 (C3D1), and End of Treatment (EOT).
• Percent Change in Plasma Levels of Phospho-AKT From Baseline [Initiation of study treatment to end of study treatment, up to 90 days.]: Phospho-AKT is a key downstream effector of the RAS/RAF/MEK signaling pathway that is proposed to be targeted by vemurafenib and sorafenib treatment. Plasma levels of phospho-AKT were measured over multiple treatment timepoints to gain molecular insight into targeted pathway suppression of the study regimen. Six patients who had blood samples available for the baseline (screen) and at least one on- or post-treatment time point were included in this analysis. Timepoints include Baseline, Cycle 2 Day 1 (C2D1), Cycle 3 Day 1 (C3D1), and End of Treatment (EOT).

Sex: All, ages: 18 Years to 100 Years

Inclusion Criteria:

1. Be able to understand and be willing to sign the written informed consent for the trial. A signed informed consent form must be appropriately obtained prior to the conduct of any trial-specific procedure.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Histologically confirmed cancer of the pancreas (KRAS mutated) with metastases and progression on at least ≥ 2 prior treatment regimens for their disease.
4. Known mutation status of KRAS and BRAF kinases. For those patients in which this has not previously been determined, the patient must have an archival tumor specimen (primary or metastatic site) available to submit to confirm KRAS and BRAF status.
5. Have a performance status of 0 or 1 on the ECOG performance scale.
6. Demonstrate adequate organ function
7. Female participants of childbearing potential must have a negative serum pregnancy test performed within 24 hours prior to receiving first dose of trial medication. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test.
8. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

   1. Not a woman of childbearing potential (WOCBP) OR
   2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of trial treatment.
9. Male participants must agree to use contraception during the treatment period and for at least 30 days after the last dose of trial treatment and refrain from donating sperm during this period.
10. Patient must have QTC of ≤500ms.
11. Subject must be able to swallow and retain oral medication
12. Measurable disease per RECIST 1.1

Exclusion Criteria:

1. Is currently participating and receiving trial therapy or has participated in a trial of an investigational agent and received trial therapy or used an investigational device within 2 weeks of the first dose of this trials' treatment.
2. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1/Day 1 or who has not recovered (i.e. NCI-CTC AE Version 5.0 ≤ Grade 1 at the time of signing informed consent) from adverse events due to a previously administered agent(s).
3. Previous BRAF inhibitor use such as vemurafenib, GSK2118436 or sorafenib.
4. If patient received major surgery, and has not yet recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
5. Previously untreated or concurrent cancer that is distinct in primary site or histology from pancreatic cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before study entry. All cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form).
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
7. Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg \[NCI-CTCAE v5.0\] on repeated measurement) despite optimal medical management.
8. Active of clinically significant cardiac disease
9. Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Evidence or history of bleeding diathesis or coagulopathy
12. Patient with any pulmonary hemorrhage/bleeding event of NCI-CTCAE v5.0 ≥ Grade 2 within 4 weeks before initiating study treatment; any other hemorrhage/bleeding event of NCI-CTCAE v5.0 ≥ Grade 3 within 4 weeks before initiating study treatment.
13. Patient with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) within 6 months of informed consent.
14. Presence of a non-healing wound, non-healing ulcer, or bone fracture
15. History of organ allograft (including corneal transplant).
16. Known or suspected allergy or hypersensitivity to any of the study drugs (sorafenib, and or vemurafenib) study drug classes, or excipients of the formulations given during the course of this trial.
17. All patients with known diagnosis of Neurofibromatosis Type 1 or other known RAS-opathies
18. Patients with uncontrolled seizures
19. Treatment with medications that have known risk of QTc interval prolongation or Torsades de Pointe (TdP) within 14 days or 5 half-lives before dose of either drug is given in this study and for the duration of the study. Refer to Appendix E for medications with a known risk of TdP.
20. Treatment with a strong or moderate CYP3A inducers (e.g, phenytoin, carbamazepine, phenobarbital, St. John's Wort \[hypericum perforatum\], dexamethasone at a dose of greater than 16 mg daily, or rifampin \[rifampicin\], and/or rifabutin) or inhibitors within 28 days before dose of either drug is given in this study and for the duration of the study. Refer to Appendix G.
21. Malabsorption or other significant bowel or stomach resections
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
24. Inability to comply with the protocol and/or not willing or not available for follow-up assessments required to assess toxicity

Participant flow

Outcome results

• Disease Control Rate (DCR) (Primary), Number, DCR, % of participants with CR/PR/SD: Vemurafenib in Combination With Sorafenib 0
• Adverse Events Possibly or Definitely Related to Vemurafenib in Combination Wit Sorafenib (Secondary), Count of participants, Participants: Vemurafenib in Combination With Sorafenib 0
• Progression-free Survival (PFS) (Secondary), Median, months: Vemurafenib in Combination With Sorafenib 1.6 (0.5 to NA)
• Overall Survival (OS) (Secondary), Median, months: Vemurafenib in Combination With Sorafenib 2.9 (0.6 to 5.4)
• Percent Change in Plasma Levels of Phospho-ERK From Baseline (Secondary), Median, Percent change from baseline, %: Vemurafenib in Combination With Sorafenib 87.4 (75.4 to 111.1)
• Percent Change in Plasma Levels of Phospho-AKT From Baseline (Secondary), Median, Percent change from baseline: Vemurafenib in Combination With Sorafenib 130.9 (92.3 to 237.3)

Adverse events

Time frame: From enrollment until 30 days following the last dose of study treatment, an average of 90 days

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Limitations of this study include a single-arm, nonrandomized study design, a small sample size, and the lack of pharmacokinetic and pharmacodynamic (PK/PD) measurements.

• Results publication: Khawaja MR, Jameson G, Cridebring D, Shannon P, Han H, Moore J, Von Hoff D, Posner RG, Hlavacek WS, Kolch W, Kholodenko BN, Rukhlenko OS, Roe DJ, Wertheim BC, Borazanci E. Phase II Trial of Vemurafenib and Sorafenib Combination in Advanced KRAS-Mutated Metastatic Pancreatic Cancer. J Immunother Precis Oncol. 2026 Feb 10;9(1):17-24. doi: 10.36401/JIPO-25-20. eCollection 2026 Feb. PMID 41766762

• Study Protocol and Statistical Analysis Plan (PDF, 2023-03-23)
• Informed Consent Form (PDF, 2023-04-05)

• Erkut Borazanci, MD, MS, Principal investigator, HonorHealth Research Institute