Phase I/II First-In-Human Open-label Trial to Assess Safety and Efficacy of STX-241 in Participants with Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC) Resistant to EGFR Tyrosine Kinase Inhibitors (TKIs).

Study Identifier:
F60087CI101
CT.gov Identifier:
NCT06567015
EudraCT Identifier:
2.02351E+11
EU Trial (CTIS) Number:
2023-510203-21-00
Study Contact Information:
(210) 593-5651 or [email protected]
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Study Summary

To determine the Recommended Phase II Dose (RP2D), explore the pharmacokinetic (PK) exposure and pharmacodynamic (PD) properties as well as assess the efficacy of STX-241, a mutant selective Central Nervous System (CNS)-penetrant fourth generation EGFR TKI, in participants with locally advanced or metastatic NSCLC that progressed during or following third generation EGFR TKI such as osimertinib due to C797X double acquired (secondary) mutations. To evaluate PFL-241/STX-241, a highly differentiated, orally bioavailable, highly selective tyrosine kinase inhibitor (“TKI”) targeting epidermal growth factor receptor (“EGFR”) Exon 19 or 21 mutations with the co-occurring C797S mutation, a known resistance mechanism to 3rd generation EGFR inhibitors. To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical efficacy of PFL-241/STX-241 as a mono therapy in patients with locally advanced or metastatic non-small cell lung cancer (“NSCLC”) harboring EGFR Exon 19 or 21mutations with the co-occurring C797S mutation. The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary antitumor activity, and efficacy of STX-241, a selective 4th-generation EGFR tyrosine kinase inhibitor (TKI). In Part 1, To study the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD). In Part 2, To identify the RP2D. Part 3, will assess the efficacy of PFL-241/STX-241 at the RP2D

The aim of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), preliminary antitumor activity, and efficacy of the selective fourth-generation EGFR tyrosine kinase inhibitor (TKI) STX-241.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Non-Small Cell Lung Cancer
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18+ years
Study Drug
N/A
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • Signed and dated informed consent for participation in the trial obtained according to International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP), and national/local regulations. Male or female ≥ 18 years of age at the time of signing informed consent. Histological confirmation of locally advanced or metastatic, EGFR-mutant (ex19del or L858R mutations) non-small cell lung cancer (NSCLC) Stage IIIB/C or IV (AJCC 8th edition) not eligible for curative intent surgery or chemoradiation. Part 1&2 Disease progression on a 3rd generation EGFR TKI-based therapy (monotherapy or in combination) received at any prior line of treatment. Tumor mutation profile: • Part 1 (backfilling component) and Part 2: Presence of C797X and absence of T790M mutations documented locally (as part of clinical practice) on a sample (blood or tissue) collected after progression on treatment with 3rd generation EGFR TKI. Part 1 (Backfilling component), Part 2: At least one measurable target lesion according to RECIST v1.1. Eastern cooperative oncology group (ECOG) performance status 0-1. Adequate organ function as defined below: Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L Platelets ≥ 75 x 10^9/L Hemoglobin ≥ 90 g/L. Serum total bilirubin ≤ 1.5 x ULN or ≤ 3.0 × ULN for participants with documented Gilbert's syndrome. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN. If the participant has liver metastases, AST and ALT ≤5 × ULN. Estimated glomerular filtration rate (GFR) ≥ 50 mL/min by CKD-EPI equation Adequate cardiac function as defined below: Mean QT interval corrected for heart rate according to Fridericia's formula (QTcF) value ≤ 470 msec for women and ≤ 450 msec for men and no history of long QT syndrome or risk factors for torsade de pointe. Left ventricular ejection fraction (LVEF) ≥ 50% . Systolic blood pressure < 150 mmHg and diastolic blood pressure < 100 mmHg Female participants of childbearing potential: Negative highly sensitive serum β-HCG test performed within 7 days prior to first dose of STX-241 (C1D1) and a negative urine pregnancy test performed prior to C1D1. Agreement to use one highly effective contraceptive method (as defined in protocol and according to local regulations), starting at screening period, throughout the trial and until at least 182 days (i.e. more than 5 estimated STX- 241 half-lives (2 days) plus 6 months (180 days)) after the last dose of STX-241. If the highly effective method of contraception is a hormonal contraceptive method, it must be supplemented by one additional effective (barrier) method of contraception. Agreement to not donate eggs (ova, oocytes) for the purpose of assisted reproduction during the trial and for a period of 182 days after the last dose of STX-241. Note: a female participant of childbearing potential is a woman who is not permanently sterilized or not postmenopausal (postmenopausal is defined as 12 months with no menses without an alternative medical cause). Male participants/partners with female spouse/partners of childbearing potential must agree to take appropriate precautions to avoid fathering a child, i.e.: Consistently use a barrier method [e.g., condom with spermicidal foam / gel / film /cream/suppository], and his female partner use a highly effective method of contraception as defined in protocol and according to local regulations), starting at screening and continuing throughout the trial period and for 92 days (ie. more than 5 estimated STX-241 half-lives (2 days) plus 3 months (90 days)) after the last dose of STX-241. Not donate sperm from Day 1 (first administration of STX-241) until at least 92 days after the last dose of STX-241. NOTE: Other protocol defined inclusion criteria may apply. In Part 1, successive cohorts of pts with locally advanced or metastatic NSCLC who have previously progressed on a third generation EGFR TKI at any line of treatment, In Part 2, pts with locally advanced or metastatic NSCLC harboring C797X mutation who have previously received a third generation EGFR TKI at any line of treatment
  • CFDA:
  • 1 Obtain a signed and dated informed consent form for participation in the trial in accordance with ICH GCP and national/local regulations.
  • 2 Men and/or women aged 18 or older at the time of signing the informed consent form, but must have reached the legal age of majority in their country/region.
  • 3 Histologically confirmed locally advanced or metastatic EGFR mutation (ex19del or L858R mutation) stage IIIB/C or IV non-small cell lung cancer (NSCLC) (AJCC 8th edition) is not suitable for radical surgery or radiotherapy/chemotherapy.
  • 4 Part 1: Disease progression following any line of prior treatment with a third-generation EGFR TKI (monotherapy or combination therapy). Part 2: Disease progression following any line of prior systemic anti-tumor therapy with a third-generation EGFR TKI (monotherapy or combination therapy) as first- or second-line systemic anti-tumor therapy, with no more than two lines of prior systemic anti-tumor therapy.
  • 5 Tumor mutation characteristics: Part 1 (backfilled): As part of clinical practice, local laboratory testing of samples (blood or tissue) collected after progression of third-generation EGFR TKI treatment showed the presence of C797X and the absence of T790M mutation. Part 2: Local laboratory testing (as part of clinical practice) of samples (blood or tissue) collected after disease progression during third-generation EGFR TKI treatment indicated the presence of C797X mutation.
  • 6 Part 1 (backfilling section) and Part 2: According to RECIST v1.1, there is at least one measurable target lesion.
  • 7 Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
  • 8 Good hematological function before the first administration of STX-241 is defined as: - Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L - Platelet count ≥ 75 x 10^9/L - Hemoglobin ≥ 90 g/L.
  • 9 Good liver function is defined as: - For subjects with documented Gilbert's syndrome, serum total bilirubin ≤1.5 × ULN or ≤3.0 × ULN. - Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × ULN. If the subject has liver metastases, AST and ALT ≤5 × ULN.
  • 10 Good renal function is defined as: - Estimated glomerular filtration rate (GFR) calculated using the CKD-EPI formula ≥ 50 mL/min.
  • 11 Good cardiac function is defined as: - A mean QT interval (QTcF) corrected for heart rate according to the Fridricia formula ≤ 470 ms (female) and ≤ 450 ms (male), with no history of long QT syndrome or risk factors for torsades de pointes. - Left ventricular ejection fraction (LVEF) ≥ 50%. - Systolic blood pressure < 150 mmHg and diastolic blood pressure < 100 mmHg.
  • 12 For women of fertility: - A negative result in a highly sensitive serum β-HCG test performed within 7 days prior to the first STX-241 (C1D1) administration and a negative result in a urine pregnancy test prior to C1D1. - Consent to use a highly effective method of contraception (defined in the protocol and according to local regulations) from the start of the screening period, throughout the trial, and for at least 182 days after the last STX-241 administration (i.e., more than 5 times the estimated STX-241 half-life (2 days) plus 6 months (180 days)). If the highly effective method of contraception is hormonal, it must be supplemented with another effective (barrier) method of contraception. - Consent not to donate oocytes (eggs, oocytes) for assisted reproductive purposes during the trial and for 182 days after the last STX-241 administration. Note: Women of fertility are those who are not permanently sterilized or are not in postmenopause (postmenopause is defined as 12 months of amenorrhea without other medical cause).
  • 13 Male subjects or partners: Male subjects/partners whose female partners are of fertility must agree to take appropriate precautions to avoid pregnancy, namely: - Always use barrier contraception [e.g., condoms with spermicide foam/gel/film/cream/suppository], and their female partners use highly effective contraceptive methods as defined in the protocol and as permitted by local regulations; continuing from the start of screening throughout the trial period and for 92 days after the last STX-241 administration (i.e., more than 5 times the estimated STX-241 half-life (2 days) plus 3 months (90 days)). - No sperm donation from Day 1 (first STX-241 administration) until at least 92 days after the last STX-241 administration.
  • 14 Willing and able to comply with all program requirements and planned procedures, including travel to the experimental research center.
  • 15 Affiliates or beneficiaries of the social security system (if applicable national regulations).
Exclusion criteria
  • Participant candidate for targeted therapies available to them (such as but not limited to therapies targeting ALK, BRAF, MET, NTRK, ROS1) as identified by local testing performed after progression to the last line of systemic therapy. Participant with rapid progressive disease eligible to receive a platinum-based chemotherapy. Participant unable ingest or digest tablets. This can be caused by any impaired gastrointestinal function or disease, such as for example: ulcerative diseases, malabsorption syndrome, small bowel resection, ileus, etc. or any condition causing uncontrolled nausea, vomiting or diarrhea. History of a primary malignancy other than NSCLC with the exception of: Participants with a previous malignancy that completed all anticancer treatment at least 2 years before signing informed consent and with no evidence of residual disease from the prior malignancy at screening. Malignancies with a negligible risk of metastasis or death (i.e. 5-year overall survival rate > 90%) that are adequately treated - Examples include, but are not limited to, completely resected basal cell carcinoma and squamous cell carcinoma of skin, melanoma in situ, curatively treated prostate cancer, breast cancer and early gastric cancer cured by endoscopic mucosal resection or endoscopic submucosal dissection. Spinal cord compression or CNS metastases that are associated with progressive neurological symptoms or require increasing doses of corticosteroids to control the CNS disease. If a participant requires corticosteroids for management of CNS disease, the dose must have been stable for 2 weeks prior to enrollment in the trial. History of hypersensitivity to active or inactive ingredients of STX-241, or drugs with a similar chemical structure or from the same class. Active, bacterial, fungal, or viral infection, including, but not limited to: Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and known Human Immunodeficiency Virus (HIV) or Acquired Immunodeficiency Syndrome (AIDS)-related illness, tuberculosis or an infection requiring systemic therapeutic treatment within 2 weeks prior to Day 1 (first administration of STX-241). Note: Participants with known HIV infection are permitted if they have controlled infection (undetectable viral load [HIV ribonucleic acid polymerase chain reaction (PCR)] and CD4 count >350 either spontaneously or on a stable antiviral regimen). For participants with controlled HIV infection, monitoring will be performed per local standards. Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending within 2 weeks of first dose of STX-241. Impaired cardiovascular function or clinically significant cardiovascular disease (either active or within 6 months prior to signing informed consent), including any of the following: Myocardial infarction, acute coronary syndromes including unstable angina, coronary/peripheral artery bypass graft, coronary angioplasty or stenting. Symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II). Cerebrovascular accident or transient ischemic attack. Symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI-CTCAE Grade ≥2. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection or psychiatric illness/social situation that would limit compliance with trial requirements. Past medical history of Interstitial Lung Disease (ILD), drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD. Past medical history of Stevens-Jonhson Syndrome (SJS) or Toxic epidermal necrolysis (TEN) or any evidence of clinically active SJS/TEN. Women who are breast feeding. Prior anticancer therapy: EGFR-targeted TKI within 7 days prior to the first dose of STX-241. Any other systemic anticancer therapy within 28 days or 5 half-lives prior to the first dose of STX-241, whichever is the shortest, but with a minimum of 14 days in all circumstances. Radiotherapy to a large field or including a vital organ (including whole brain radiotherapy or stereotactic radiosurgery to brain) within 14 days before the first dose of STX-241. Live attenuated vaccine received within 30 days prior to the first dose of STX-241. Any toxicities from prior therapy with a NCI-CTCAE Grade ≥1 at the time of the first dose of STX-241 (C1D1). Exceptions include alopecia (any grade), fatigue with a Grade ≤2, and peripheral neuropathy with a Grade ≤2. Major surgical procedure within 14 days of the first dose of STX-241 (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures). Sequelae of surgical procedures must have resolved, including adequate wound healing, prior to the first dose of STX-241. Treatment with a prohibited medication or herbal remedy known to be strong CYP1A2 or CYP3A4 inducers, strong CYP1A2 or CYP3A4 inhibitors, sensitive CYP1A2, CYP2B6 and CYP3A4 substrates, sensitive MATE1 and OATP1B1 substrates and proton pump inhibitors (PPI) and H2 antagonists unless discontinued prior to the first administration of STX-241 within the following timeframe: At least 5 half-lives plus 14 days for strong CYP inducers. At least 5 half-lives for CYP inhibitors, CYP/transporter substrates, proton pump inhibitor (PPI) and H2 antagonists. Participation in a clinical trial with administration of an investigational drug within 5 half-lives plus 14 days of the investigational drug, before the first dose of STX-241. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e. g, could compromise the participant's well-being) or would prevent, limit, or confound the protocol-specified assessments. Employee or family member of the investigator or site staff. NOTE: Other protocol defined exclusion criteria may apply.
  • CFDA:
  • 1 Part 1: Candidate subjects receiving available targeted therapies, such as (but not limited to) targeting ALK, BRAF, MET, NTRK, and ROS1, were identified through local laboratory testing following progression of last-line systemic therapy. Part 2: Candidate subjects eligible for available targeted therapies, including but not limited to targeted therapies targeting ALK, BRAF, MET (ex14 mutation or amplification), NTRK, ROS1, and HER2 (mutation or amplification), whose targets were identified through local laboratory testing following progression of third-generation EGFR-TKI therapy.
  • 2 Subjects whose disease is progressing rapidly and who are eligible to receive platinum-based chemotherapy.
  • 3 Subjects may be unable to swallow or digest tablets and capsules. This may be caused by any impaired gastrointestinal function or disease, such as ulcerative diseases, malabsorption syndrome, small bowel resection, intestinal obstruction, or any condition that causes uncontrollable nausea, vomiting, or diarrhea.
  • 4 A history of primary malignancy other than NSCLC is acceptable, except in the following cases: - The subject had a history of malignancy, completed all radical anticancer therapies at least 2 years prior to signing the informed consent form, and there is no evidence of residual lesions from the previous malignancy at the time of screening. - The risk of metastasis or death is negligible (i.e., 5-year overall survival > 90%) and the malignancy has been adequately treated. Examples include, but are not limited to, completely resected basal cell carcinoma and squamous cell carcinoma of the skin, cured in situ melanoma of the skin, cured prostate cancer, breast cancer, and early gastric cancer cured by endoscopic mucosal resection or endoscopic submucosal dissection.
  • 5 Spinal cord compression or CNS metastasis associated with progressive neurological symptoms or requiring progressively increasing doses of corticosteroids to control CNS disease. If a subject requires corticosteroid treatment for CNS disease, their dose must have been stable for 2 weeks prior to enrollment in this trial.
  • 6 There is a history of allergy to the active or inactive components of STX-241 or to drugs with similar chemical structures or classes.
  • 7 Active bacterial, fungal, or viral infection, including but not limited to: HBV, HCV and known HIV or AIDS-related diseases, tuberculosis, or infection requiring systemic treatment within 2 weeks prior to the first dose of STX-241 (C1D1).
  • 8 A positive RT-PCR test for SARs-CoV-2 or SARs-CoV2 variants within 2 weeks prior to the first STX-241 dose (C1D1), or suspected infection with SARs-CoV2 or SARsCoV2 variants, is pending confirmation.
  • 9 Impaired cardiovascular function or clinically significant cardiovascular disease (active or within 6 months prior to signing the primary informed consent form), including any of the following: - Myocardial infarction, acute coronary syndrome (including unstable angina), coronary/peripheral artery bypass grafting, coronary angioplasty, or stent implantation; - Symptomatic congestive heart failure (New York Heart Association classification ≥ II); - Cerebrovascular accident or transient ischemic attack; - Symptomatic bradycardia requiring antiarrhythmic drug therapy; - Persistent arrhythmia with NCI-CTCAE classification ≥ 2.
  • 10 Control adverse complications, including but not limited to mental illnesses or social conditions (including alcoholism) that may limit trial compliance.
  • 11 A history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD.
  • 12 A history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or any evidence of clinically active SJS/TEN.
  • 13 Women who are breastfeeding.
  • 14 Previous anticancer therapy: - Received an EGFR TKI within 7 days prior to the first STX-241 dose. - Received any other systemic anticancer therapy within 28 days prior to the first STX-241 dose or within 5 half-lives of the anticancer therapy (whichever is shorter, but not less than 14 days). - Received extensive or major organ radiation therapy (including whole-brain radiation therapy or stereotactic radiosurgery of the brain) within 14 days prior to the first STX-241 dose.
  • 15 Receive the live attenuated vaccine within 30 days prior to the first STX-241 dose (C1D1).
  • 16 At the time of the first STX-241 dose (C1D1), any toxicity of prior treatment must be NCI-CTCAE >1. Exceptions include alopecia (any grade), fatigue ≤ grade 2, and peripheral neuropathy ≤ grade 2.
  • 17 Major surgical procedures must have been performed within 14 days prior to the first STX-241 dose (C1D1). Procedures such as central venous catheter placement, tumor biopsy, and feeding tube placement are not considered major surgical procedures. Post-operative sequelae must have resolved, including adequate wound healing prior to the first STX-241 dose.
  • 18 Treatment with prohibited drugs or herbal remedies, such as potent CYP3A4/1A2 inducers and inhibitors, CYP1A2, 2B6, and 3A4 sensitive or moderately sensitive substrates, OATP1B1 substrates, metformin (MATE1 substrates), proton pump inhibitors (PPIs), and H2 antagonists, must be discontinued within the following timeframes prior to the first dose of STX-241: - For potent CYP inducers, at least 5 half-lives plus 14 days. - For CYP inhibitors, CYP/transporter substrates, PPIs, and H2 antagonists, at least 5 half-lives.
  • 19 Participants in clinical trials of the investigational drug must be within 5 half-lives plus 14 days prior to the first dose of STX-241 (C1D1).
  • 20 Any of the following situations exist: participation in the study is not in the best interests of the participants (e.g., may harm the health of the participants) or may hinder, limit or obstruct the assessments prescribed by the protocol (e.g., any psychological, family, social or geographical circumstances that may hinder adherence to the trial protocol and follow-up schedule).
  • twenty one Subjects are family members of the researcher or any assistant, colleague, or staff member (secretary, nurse, technician) who assists in the trial or may otherwise represent a conflict of interest. Subjects are eligible to participate in the study only after obtaining informed consent from an appropriately qualified individual who is completely independent of such a relationship.
  • twenty two Subjects may lose their freedom or be placed under guardianship through administrative or legal decisions.
  • twenty three Part 2: Subjects who have received first- or second-generation EGFR TKI treatment.

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Ramon Yarza
Status
Recruiting
Condition(s) Treated at Site
Non-Small Cell Lung Cancer