KTTA Stock Research Snapshot: Pipeline, Catalysts, and Cash Runway

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Estimated cash runway: Runway > 12 months.

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Scientific Context

• catalyst_type | Data Readout
• conditions | RAS Mutation | NF1 Mutation | RAF Mutation | Advanced Solid Tumors
• conditions | NF1 Mutation | Neurofibroma Plexiform | Neurofibroma, Plexiform | Neurofibromatosis Type 1 (NF1)-Related Plexiform Neurofibromas (PNs) | Neurofibromatosis Type 1 (NF1)
• 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 without an existing prior genetic test result or adequate tumor tissue sample must agree to provide tumor tissue via biopsy (paraffin section or fresh tissue specimens) that will be sent for analysis to confirm eligibility. 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 3 weeks of enrollment. 2. Having received chemotherapy, radiotherapy, major surgery, targeted therapy, immunotherapy, or other antitumor treatment within 21 days of enrollment or five half-lives of the administered therapy, whichever occurs first. 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 known corrected QT (QTc) interval prolongating medication within 7 days 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 currently active 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).
• eligibility_criteria | Inclusion Criteria: 1. Participant is capable of providing informed consent, which includes compliance with the requirements, prohibitions and restrictions listed in the informed consent form. 2. Participant 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. Participant must be at least 18 years of age at the signing of the informed consent form (ICF). 4. Participant must be able to swallow oral medication. 5. Performance status: Participant must have a Karnofsky performance level of ≥70%. Note: Participants who are wheelchair bound because of paralysis secondary to a PN should be considered ambulatory when they are in the wheelchair. Similarly, participants with limited mobility secondary to the need for mechanical support (such as an airway PN requiring tracheostomy or CPAP) will also be considered ambulatory for the purposes of this study. 6. Participant has been diagnosed with NF1 based upon the following diagnostic criteria: a. Clinical and imaging confirmation meeting at least two of the following NF1 diagnostic criteria in accordance with the clinical NIH consensus criteria: i. ≥ Six cafe-au-lait macules \> 1.5 cm in maximum diameter ii. Axillary and/or inguinal freckling iii. ≥ Two neurofibromas of any type, or ≥ 1 plexiform neurofibroma; iv. An optic pathway glioma (prior diagnosis without concurrent disease is acceptable) v. ≥ Five Lisch nodules (iris hamartomas). Note: must be confirmed on slit lamp exam by an ophthalmologist if this is one of only two criteria met for diagnosis vi. A distinctive bony lesion such as dysplasia of the sphenoid bone or dysplasia or thinning of long bone cortex vii. Biologic parent with confirmed diagnosis of NF1 viii. Genetic testing demonstrating a pathogenic NF1 germline mutation per CLIA-certified laboratory (or equivalent) testing. 1\. Note: NF1 germline pathologic mutation positive must either be confirmed by the central laboratory or have documentation of NF1 mutation issued by a CLIA-certified laboratory (or equivalent). 2. No concern by the Investigator that an NF1 mimic, including but not limited to Noonan Syndrome, Legius Syndrome, or schwannomatosis could potentially serve as a more likely diagnosis 7\. Participants satisfying the NF1 diagnostic criteria outlined in Inclusion Criterion #6 must also meet one of the following criteria: a. Participant has at least one symptomatic PN ("Target PN") measuring at least 3 cm on maximal cross-sectional (axial) diameter that is judged by the Investigator to be likely responsible for participant symptoms (such as pain, deformity, or neurologic disability), and unable to be completely resected without causing substantial damage/functional deficit, or unsuitable for surgery with high surgical risks. b. Participant has an incompletely resected symptomatic PN with a postoperative residual of at least 15% of the primary lesion and measuring at least 3 cm on cross-sectional (axial) diameter. c. Participant has a recurrent symptomatic PN measuring at least 3 cm in maximal cross-sectional (axial) dimension after prior resection. 8\. Participants should have a minimum of seven measurable CN measuring 6-15 mm (if participants satisfy Inclusion Criterion #6 and have no CN or less than 7 CN they still might be considered for the study as judged by the Investigator and Sponsor). 1. Measurable is defined as: 1. non-pedunculated (no stalk) 2. surrounded by visually uninvolved skin and not in physical contact with another CN, 3. measuring between 6 and 15 mm in the longest diameter and exophytic on visual exam (not macular). 2. At least seven CN should be located on the trunk, neck, and/or limbs measuring between 6 and 15 mm in maximal diameter, and "measurable" as per the definition listed above. 3. Participants with CN meeting the above criteria will undergo optional resections of at least two CN that meet eligibility criteria. If participant is willing to accept additional CN resections, this is permitted for up to four additional lesions after completion of six PAS-004 treatment cycles or after early withdrawal as long as there are sufficient lesions to allow efficacy assessment. 9\. Participant must be able and willing to undergo serial MRI scans as outlined in the study protocol. Note: Anxiolytic medication or pain medication as deemed clinically appropriate by the Investigator is permissible for the purposes of managing anxiety, claustrophobia, and pain during MRI. 10\. Participant must be able and willing to undergo serial 2-D and where available 3-D photography as well as caliper measurements as outlined in the study protocol. 11\. Participant must have an international normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN. 12\. Participant must have adequate organ and bone marrow function at screening as indicated by the following laboratory value ranges: a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L b. Hemoglobin ≥ 90 g/dL c. Platelets ≥ 100 × 109/L d. Serum total bilirubin ≤ 1.5 × ULN for age (≤ 3.0 × ULN in participants with Gilbert's syndrome) e. Serum total bilirubin ≤ 1.5 × ULN (Serum total bilirubin can be ≤ 3.0 × ULN if participants have hemolysis or congenital hemolytic diseases) f. Aspartate aminotransferase (AST) ≤ 2.0 × ULN g. Alanine aminotransferase (ALT) ≤ 2.0 × ULN h. Albumin ≥ 3 g/dL i. Creatinine clearance ≥ 60 mL/min 13\. Participant must either agree to maintain abstinence (no heterosexual intercourse), or to use one highly effective form of contraception during study treatment and for at least 90 days after the last dose of investigational product (IP). Sperm-producing participants must agree not to donate sperm while receiving IP and for at least 90 days after the last dose of IP. Exclusion Criteria: 1. Participant has participated in another interventional clinical study within 28 days of starting PAS-004. 2. Participant has received chemotherapy for any indication within 90 days of starting PAS-004. 3. Participant has ongoing side effects from prior chemotherapy that are worse than mild (except alopecia). ("Mild" is defined as Asymptomatic or mild symptoms, clinical or diagnostic observations only, or intervention not indicated.) 4. Participant has received treatment with any PN-directed drug or biologic therapy within 14 days of starting PAS-004. 5. Participant has received treatment with a strong CYP3A4 inhibitor or inducer, or moderate inducers for CYP2C8 and CYP2C9 within 14 days of starting PAS-004, or any drug considered a major substrate of the enzymes above with a narrow therapeutic index except for topical skin use, as judged by the Investigator and Sponsor. 6. Participant has received growth factors to increase the number or function of platelets or white blood cells within 7 days of starting PAS-004. 7. Participant has received radiotherapy, major surgery, or immunotherapy within 28 days of starting PAS-004. 8. Participant has malignant tumors associated with NF1 requiring chemotherapy, radiotherapy, or surgery, such as intermediate- to high-grade gliomas or malignant peripheral nerve sheath tumors. 9. Participant has a current malignancy (excluding cured non-melanomatous skin cancer, breast carcinoma in situ, or cervical cancer in situ) or has history of malignancy requiring active treatment within the past 5 years (excluding cured non-melanomatous skin cancer, breast carcinoma in situ, and cervical cancer in situ). Other tissue-limited low stage cancers can be assessed by the Sponsor for possible inclusion on a per-participant basis. 10. Participant has uncontrolled hypertension defined as blood pressures \>150/90 mmHg on repeat examinations despite maximal medical management. Note: Participants with controlled hypertension with anti-hypertension therapy are permitted, as judged by the Investigator and Sponsor. 11. Participant has active dysphagia, digestive system disease, malabsorption syndrome, or other conditions that might affect the absorption of PAS-004. 12. Participant has previous or current retinal vein occlusion (RVO), retinal pigment epithelial detachments (RPED), clinically active glaucoma, or other significant abnormality in screening ophthalmic examination. 13. Participant has interstitial pneumonia, NF1-related pulmonary disease, including existing clinically significant radiation pneumonitis. 14. Participant has impaired cardiac function or cardiac disease as indicated by: 1. Average QTc interval \> 480 ms calculated using the Fridericia's QT interval correction formula. 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. 4. Known concurrent clinically significant coronary artery disease, cardiomyopathy, or severe valvular disease. 5. Echocardiogram or multi-gated acquisition (MUGA) scan performed during the screening showing impaired left ventricular ejection fraction (LVEF) \< 45%. 15. Participant has taken a QTc-prolonging medication within seven days of IP 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 IP initiation. 16. Participant has an uncontrolled bacterial, fungal, or viral infections, including active hepatitis B (hepatitis B virus surface antigen positive and hepatitis B virus DNA \> 1000 IU/ml or meeting the study site's diagnostic criteria for active hepatitis B infection), hepatitis C (hepatitis C virus RNA positive), or human immunodeficiency virus (HIV) infection with detectable viral load. 17. Any clinically significant active or known history of liver disease or known hepatobiliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). 18. Participant has a known hypersensitivity to PAS-004, its excipients, or another MEK 1/2 inhibitor. 19. Participant is pregnant or lactating. 20. Participant has a clinically significant condition that, in the opinion of the investigator, would preclude study participation or compliance with safety requirements. 21. Participant is unable to attend in-person clinic visits per clinical site guidelines and restrictions.