PAS-004 in Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT06299839
• Recruitment Status: Recruiting
• First Posted: March 8, 2024
• Last Update Posted: March 8, 2024
• Sponsor: Pasithea Therapeutics Corp.
• Information provided by (Responsible Party): Pasithea Therapeutics Corp.

Tracking Information

• First Submitted Date: February 12, 2024
• First Posted Date: March 8, 2024
• Last Update Posted Date: March 8, 2024
• Actual Study Start Date: February 29, 2024
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 1, 2024)

• Evaluation of dose limiting toxicities (DLTs) [ Time Frame: Day 1 through Day 35 (Cycle 1) ]
  Pre-defined DLTs will be assessed for dose escalation and expansion determinations.
• Evaluation of adverse events (AEs) [ Time Frame: Screening through Day 1 through Day 35 (Cycle 1), and 30 days after discontinuation of study drug ]
  The number and severity of AEs will be evaluated for dosing cohorts to inform dose escalation and expansion decisions, and support selection of a preliminary recommended phase 2 dose (RP2D).
• Evaluation of AEs leading to discontinuation of investigational product (IP), PAS-004. [ Time Frame: Screening through Day 1 through Day 35 (Cycle 1), and 30 days after discontinuation of study drug ]
  The number and severity of AEs leading to discontinuation of study drug will be evaluated for dosing cohorts to inform dose escalation and expansion decisions, and support selection of a preliminary recommended phase 2 dose (RP2D).
• Evaluation of hematology laboratory parameters [ Time Frame: Screening through Day 1 through Day 35 (Cycle 1), and 30 days after discontinuation of study drug ]
  Lab parameters will be evaluated for to assess the safety profile of the study drug, and support selection of a preliminary recommended phase 2 dose (RP2D).
• Evaluation of clinical chemistry laboratory parameters [ Time Frame: Screening through Day 1 through Day 35 (Cycle 1), and 30 days after discontinuation of study drug ]
  Lab parameters will be evaluated for to assess the safety profile of the study drug, and support selection of a preliminary recommended phase 2 dose (RP2D).

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted

Current Secondary Outcome Measures (submitted: March 1, 2024)

• Apparent terminal elimination half-life (t1/2) in Plasma [ Time Frame: Cycle 1: Day 1 and Day 22 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 4, 8, 15, 29 and 35 (predose) ]
• Peak Plasma Concentration (Cmax) [ Time Frame: Cycle 1: Day 1 and Day 22 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 4, 8, 15, 29 and 35 (predose) ]
• Plasma predose or trough concentration (Ctau/Ctrough) [ Time Frame: Cycle 1: Day 22 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 8, 15, 29 and 35 (predose) ]
• Time of maximum plasma concentration (Tmax) [ Time Frame: Cycle 1: Day 1 and Day 22 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 4, 8, 15, 29 and 35 (predose) ]
• Area under the concentration versus time curve from time zero to the last sampling time with quantifiable analyte (AUC0-t) [ Time Frame: Cycle 1: Day 1 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 4 ]
• Area under the concentration versus time curve from time zero extrapolated to infinity if possible (AUC0-∞) [ Time Frame: Cycle 1: Day 1 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 4 ]
• Area under the concentration versus time curve for the dosing interval, assuming steady state has been reached and duplicating the predose concentration for the 24 hour postdose concentration (AUC0-tau) [ Time Frame: Cycle 1: Day 22 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 8, 15, 29 and 35 (predose) ]
• Apparent total plasma clearance if possible (CL/F) [ Time Frame: Cycle 1: Day 1 (predose, and 30 min, 1 hr, 2 hr, 3 hr, 5 hr, 8 hr and 24 hr post-dose), Day 4, and 8 (predose) ]
• Evaluation of the percentage of extracellular signal-regulated kinase phosphorylation (pERK) inhibition from baseline [ Time Frame: Day 1 through Day 35 (Cycle 1) ]
• Evaluation of the objective response rate (ORR) [ Time Frame: Screening, Day 35 (Cycle 1), and every 9 weeks thereafter ]
  The proportion of participants achieving a partial response (PR) or complete response (CR) per response evaluation criteria in solid tumors (RECIST) 1.1 criteria.
• Evaluation of progression-free survival (PFS) [ Time Frame: Cycle 1 Day 1 to date of death, up to 25 months from last participant enrolled ]
  The time from first dose of IP to the date of documented disease progression or date of death due to any cause (whichever occurs first).
• Evaluation of overall survival (OS) [ Time Frame: Cycle 1 Day 1 to date of death, up to 13 months from last participant enrolled ]
  The time from first dose of IP to the date of death due to any cause.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: PAS-004 in Patients With Advanced Solid Tumors
• Official Title: A Phase 1 Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PAS-004, a MEK (1/2) Inhibitor, in Patients With MAPK Pathway-driven Advanced Solid Tumors With a Documented RAS, NF1, or RAF Mutation or Patients Who Have Failed BRAF/MEK Inhibition

Brief Summary

The main purpose of this clinical trial is to test PAS-004 in people with advanced solid tumors with rat sarcoma virus (RAS), neurofibromatosis type I (NF1), or rapidly accelerated fibrosarcoma (RAF) mutations. The main questions it aims to answer are:

• How well participants are able tolerate different doses of PAS-004, and
• What side effects PAS-004 might have.

Study participants will have regular visits to the study doctor and be asked to have tests and exams done to check on their health and safety. Everyone participating in the study will take PAS-004 by mouth as a single dose, followed by one week observation, then once a day during the study, in 28-day cycles. Participants will continue on daily PAS-004 for up to 2 years, or until:

• They decide to withdraw from the study, or
• They experience unacceptable side effects, or
• Their disease progresses, or another illness interferes with taking the study drug, or
• The sponsors stops the study.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:

3+3 dose expansion

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• RAS Mutation
• NF1 Mutation
• RAF Mutation
• Advanced Solid Tumors

Intervention

Drug: PAS-004

A mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK kinase, or MEK) 1/2 inhibitor presented in 1 mg and 10 mg strength capsules, intended for oral administration once daily.

Study Arms

Experimental: PAS-004

Sequential dose escalation: 2 mg, 4 mg, 6 mg, 9 mg, 12 mg, 15 mg, and 18 mg

Intervention: Drug: PAS-004

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 1, 2024): 42
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: February 2027
• Estimated Primary Completion Date: December 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Capable of giving signed informed consent which includes compliance with the requirements, prohibitions and restrictions listed in the informed consent form (ICF).
2. Patient has been informed both verbally and in writing about the objectives of the clinical study, the methods, the anticipated benefits, the potential risks, and the discomfort to which they may be exposed and has given written consent to participation in the study prior to study start and any study-related procedure.
3. Patient must be at least 18 years of age at the time of signing the ICF.
4. Patient must be able to swallow oral medication.

5. Patient with histologically or cytologically diagnosed mitogen-activated protein kinase (MAPK) pathway driven advanced solid tumors with all of the following characteristics:

   1. Tumor cannot be surgically resected
   2. Patient has failed or is ineligible for standard of care therapy
   3. Patient has no available treatment options with known clinical benefit
   4. Documented evidence of rat sarcoma virus (RAS), neurofibromatosis type I (NF1), and/or rapidly accelerated fibrosarcoma (RAF) mutations. Patients with RAF mutations must have previously failed v-Raf murine sarcoma viral oncogene homolog B (BRAF) / MEK inhibition.
6. Prior to enrollment, patients must agree to provide tumor tissue via biopsy (paraffin section or fresh tissue specimens) that will be sent for analysis to confirm eligibility, if no genetic test data or an adequate tumor tissue sample is available from within the 12 months prior to ICF signature.
7. Patient must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix B).
8. Patient must have an estimated life expectancy of at least 12 weeks in the opinion of the Investigator at the time of informed consent.

9. Patient must have adequate organ function at screening as indicated by the following laboratory value ranges:

   1. Serum total bilirubin ≤ 1.5 × upper limit normal (ULN) (Serum total bilirubin can be ≤ 3.0 × ULN if patients have hemolysis or congenital hemolytic diseases)
   2. Aspartate aminotransferase (AST) ≤ 2.5 × ULN or 5 × ULN for patient with liver metastases
   3. Alanine aminotransferase (ALT) ≤ 2.5 × ULN or 5 × ULN for patient with liver metastases
   4. Albumin ≥2 mg/dL
   5. Creatinine clearance ≥ 45 mL/min (as calculated per Cockcroft-Gault)
   6. Absolute neutrophil count (ANC) ≥ 1.5×109/L
   7. Platelets ≥ 100×109/L
   8. Hemoglobin ≥ 90 g/L (Note: Criteria must be met without a transfusion within 2 weeks of obtaining the sample)
10. Patient must agree to maintain abstinence (no heterosexual intercourse) or use a highly effective form of contraception during study treatment and for at least 90 days after the last dose of IP. Male patients must agree not to donate sperm while receiving IP and for at least 90 days after the last dose of IP.

Exclusion Criteria:

1. Participation in another therapeutic clinical trial within 4 weeks of enrollment.
2. Having received chemotherapy, radiotherapy, major surgery, targeted therapy, immunotherapy, or other antitumor treatment within 4 weeks of enrollment.

3. Known or active central nervous system metastases.

   1. Patients with untreated brain metastases ≤ 30 mm that are asymptomatic, do not have significant edema, and do not require steroids or anti-seizure medications are eligible after discussion with the Medical Monitor.
   2. Patients with previously treated brain metastases may participate provided they are stable after treatment and without evidence of progression by imaging for at least 4 weeks prior to the first dose of IP administration and are not using corticosteroids for at least 7 days prior to IP administration.
   3. Patients with confirmed leptomeningeal disease are to be excluded.
4. Unresolved toxicity from prior antitumor therapy defined as AEs > Grade 2 according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, except for alopecia; neurotoxicity AEs of patients who have received prior chemotherapy needs to be restored to Grade 2 or below. Patients with ≥ Grade 3 bleeding within 4 weeks of first study treatment dose should be excluded.
5. Taken a medication that is a strong cytochrome P450 (CYP3A) inhibitor or inducer within 14 days of initiation of study therapy dosing.
6. Taken a corrected QT (QTc) interval prolongating medication within 7days of initiation or longer if the half-life of the QTc prolonging medication is such that the drug is not cleared from the body within 7 days (5 half-lives) of initiation of study therapy dosing.
7. Active dysphagia, digestive system disease, malabsorption syndrome, or other conditions affecting PAS-004 absorption.
8. Previous or current retinal vein stenosis, retinal detachment, central retinal vein occlusion, or glaucoma.
9. Active interstitial pneumonia, including clinically significant radiation pneumonitis.

10. Impaired cardiac function or cardiac disease as indicated by:

    1. Average QTc interval > 470 ms as calculated according to the QTc formula of the instrument at the research center where electrocardiogram (ECG) measurements are performed.
    2. Grade ≥ 3 congestive heart failure per New York Heart Association (NYHA) guidelines.
    3. Clinically significant arrhythmias, including but not limited to, complete left bundle branch conduction abnormalities and 2nd degree atrioventricular block.
11. Pregnant or lactating female patients.
12. Known allergy or hypersensitivity to the investigational product (IP), including excipients, or history of severe adverse reaction to any drug, or sensitivity to components of the IP.
13. Clinically active bacterial, fungal, or viral infections, hepatitis B (hepatitis B virus surface antigen positive and hepatitis B virus DNA over 1000 IU/ml) or hepatitis C (hepatitis C virus RNA positive), human immunodeficiency virus infection (HIV positive).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT06299839
• Other Study ID Numbers: PAS-004-102; 2024-510900-34 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Pasithea Therapeutics Corp.
• Original Responsible Party: Same as current
• Current Study Sponsor: Pasithea Therapeutics Corp.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Graeme Currie, PhD; Pasithea Therapeutics Corp.

• PRS Account: Pasithea Therapeutics Corp.
• Verification Date: March 2024