IRB Study Number 22-1205
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To determine the maximum tolerable dose (MTD), if one exists, and the recommended phase 2 dose (RP2D) of BDTX-1535 as monotherapy for patients with NSCLC or GBM.
• To determine MTD, if one exists, and the RP2D of BDTX-1535 in combination with TMZ for patients with GBM.
Secondary Objectives
• To characterize the pharmacokinetics (PK) and circulating metabolite profile of BDTX-1535 following single and multiple dosing.
• To assess the safety and tolerability of BDTX-1535 as monotherapy and with TMZ.
• To assess the preliminary antitumor effect of BDTX-1535 as monotherapy in patients EGFR mutated NSCLC or GBM, and in combination with TMZ for patients with GBM.
• To assess the additional measures of efficacy following treatment with BDTX-1535 as monotherapy for patients with NSCLC or GBM.
• To assess the effect of food on the PK of BDTX-1535.
• To characterize the PK of TMZ and BDTX-1535 when administered in combination
• To investigate the PK of BDTX-1535 using population PK (PopPK) methods and explore correlations between PK, response, and/or safety findings.
Inclusion Criteria
Adults 18 years of age or older or as permitted by applicable local regulations at the time of providing informed consent.
Patients with GBM or NSCLC who meet the disease-specific criteria and have disease progression after treatment with available therapies that are known to confer clinical benefit, or who refuse or are intolerant to treatment (excluding the patients with treatment-naïve NSCLC, for which one previous cycle of chemotherapy or immune checkpoint inhibitor is permitted).
This inclusion criterion was removed from the protocol with Amendment 4 (Version 5).
Adequate bone marrow or organ function as demonstrated by all the following laboratory values:
a. Estimated (using the Cockcroft-Gault equation) or measured creatinine clearance ≥ 60 mL/min, or Serum Creatinine within normal limits per institution.
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 × ULN. AST or ALT ≤ 5.0 × ULN in the presence of liver metastases.
c. Total bilirubin < 1.5 × ULN (for patients with Gilbert’s syndrome, bilirubin < 3.0 × ULN is allowed).
d. Absolute neutrophil count (ANC) > 1000 cells/μL
e. Hemoglobin > 8.5 g/dL. (Note: transfusion is allowed up to 1 week prior to enrollment)
f. Platelet count > 100,000/μL. (Note: transfusion is allowed up to 1 week prior to enrollment)
For patients who are being treated with corticosteroids, the dose should be a maximum of 4 mg dexamethasone (or equivalent) per day and stable or decreasing during the 5 days prior to start of study drug.
Life expectancy of ≥ 3 months
Women of child-bearing potential must have documentation of a negative serum pregnancy test (beta-human chorionic gonadotropin [β-hCG]) prior to first dose of study treatment.
Women of child-bearing potential and male patients whose sexual partners are women of child-bearing potential, must agree to use a highly effective method of contraception to avoid pregnancy during the study and for ≥ 90 days after the last dose of study drug administration. Male patients must refrain from donating sperm during the treatment period. See Appendix F for additional details.
Note: Highly effective birth control includes 1) oral, implantable, or injectable combined hormonal (estrogen- and progesterone-containing) or progesterone-only contraceptive associated with inhibition of ovulation; 2) intrauterine device; 3) intrauterine hormone-releasing system; or 4) bilateral tubal occlusion, vasectomized partner, or sexual abstinence.
Inclusion Criteria (#9 to 13) Required for Recurrent GBM Patients Only (Dose Escalation Only)
In addition to the common inclusion criteria above, patients with recurrent GBM must also meet the following inclusion criteria.
Histologically confirmed diagnosis of GBM according to 2021 WHO criteria wild-type isocitrate dehydrogenase (IDHwt) IDH GBM and astrocytoma with molecular features of GBM.
A radiological diagnosis of recurrent disease (defined meeting at least one of the following criteria as compared to the post radiotherapy MRI: tumor progression in radiotherapy field at least 3 months post end of radiotherapy, tumor progression outside of the radiation field, or tumor progression identified by surgery/biopsy) following available standard of care therapy of surgery, radiation, and/or temozolomide. Disease may be evaluable or measurable for dose escalation cohorts but must be measurable by Response Assessment in Neuro-oncology (RANO) criteria for enrollment on the disease specific expansion.
Tumor evidence of EGFR alterations including variants, or mutations with or without amplifications as determined in a local laboratory by NGS (see Appendix A for validated EGFR alterations).
Note: assay must be performed in a validated laboratory setting (eg, CLIA or comparable certification).
For patients who had surgical resection, there must be adequate recovery from surgery and evaluable or measurable disease following surgery or if the disease progression is obvious in the opinion of the investigator.
Have a Karnofsky performance status ≥ 60% (ie, the patient must be able to care for themselves with occasional help from others) (Chambless 2015).
Inclusion Criteria (#14 to 18) Required for Advanced/Metastatic NSCLC Patients Only
Patients with advanced/metastatic NSCLC must meet all of the following inclusion criteria, in addition to the common inclusion criteria applicable for all patients.
Histologically or cytologically confirmed NSCLC, without small cell lung cancer transformation.
Locally advanced or metastatic disease, without or with asymptomatic CNS metastases. Disease may be evaluable or measurable for dose escalation cohorts but must be measurable by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria for enrollment on the disease specific expansion cohorts.
Disease progression following or intolerance of standard of care (excluding patients in the treatment-naïve non-classical driver cohort):
a. Phase 1 Dose escalation cohorts only:
• NSCLC with a non-classical driver EGFR mutation (eg, G719X) following an EGFR inhibitor treatment (3rd generation preferred; other generations acceptable).
• NSCLC with an acquired resistance EGFR mutation (eg, C797S), following a 3rd generation EGFR inhibitor in the 1st line setting (in the absence of concurrent T790M).
b. Phase 2 Dose expansion cohorts only:
• Cohort 1 (Non-Classical driver cohort): Advanced/metastatic NSCLC with a non-classical driver EGFR mutation (eg, G719X) following up to 2 lines of therapy with only 1 prior EGFR TKI regimen (third-generation preferred; other approved EGFR TKI acceptable);
• Cohort 2 (Acquired resistance C797S cohort): Advanced/metastatic NSCLC with the acquired resistance C797S EGFR mutation following up to 2 lines of therapy, including only one EGFR TKI, which must be a third generation EGFR TKI (eg osimertinib);
Note: Prior targeted therapies for 3rd generation EGFR TKI resistance (eg, amivantamab, HER3-ADC, etc) and all experimental treatments are excluded for the Phase 2 patient populations.
• Cohort 3 (First-line non-classical driver cohort): Treatment-naïve advanced/metastatic NSCLC with a non-classical driver EGFR mutation (1 cycle of chemotherapy or immune checkpoint inhibitor are permitted).
Note: For all cohorts, excluding the first line non-classical driver cohort, progression while receiving adjuvant therapy with an EGFR inhibitor treatment is not considered a line of treatment for this study.
- Identification of one (or more) of the following EGFR mutations by NGS (see Appendix A for list of validated mutations) as determined by a local assay performed in a validated laboratory setting (eg, CLIA or comparable certification) in the absence of other known resistance mutations (eg, T790M, MET):
a. Non-classical driver EGFR mutations (eg, G719X or other mutations validated by the Sponsor).
b. EGFR acquired resistance mutation (eg, C797S) to a 3rd generation EGFR TKI.
− Note: For dose expansion cohort patients, test must be obtained after progression on the most recent therapy; at the time of diagnosis for the patients in Cohort 3 only.
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (Oken 1982).
Exclusion Criteria
Known resistant mutations in tumor tissue or ctDNA, including EGFR T790M, EGFR exon 20 insertion mutations, MET (including MET amplification), KRAS, or HER2 (C805S, T798I, or T862A). Patients with suspected small cell transformation are not eligible.
Dose escalation Only: GBM patient treated with a prior EGFR inhibitor. (Note: this specific exclusion does not apply to NSCLC since patients with NSCLC are required to have had appropriate approved EGFR inhibitors prior to enrollment excluding the first line non-classical driver cohort).
Symptomatic leptomeningeal disease.
Symptomatic brain metastases or spinal cord compression requiring increasing corticosteroids or urgent clinical intervention.
Unresolved Grade 2 or greater toxicity from prior therapy (excluding alopecia, lymphopenia, or hypothyroidism or Grade 2 neuropathy adequately managed with stable medication) according to the NCI CTCAE Version 5.0.
Significant cardiovascular disease, including:
a. Cardiac failure defined as New York Heart Association Class III or IV or left ventricular ejection fraction (LVEF) < 50% or below the lower limit of the Institution’s normal range.
b. Myocardial infarction, severe or unstable angina within 6 months prior to baseline.
c. Significant thrombotic or embolic events within 3 months prior to baseline including, but not limited to, stroke or transient ischemic attack.
Note: Catheter-related thrombosis and deep vein thrombosis are not a cause for exclusion.
d. History or presence of any uncontrolled cardiovascular disease.
- Clinically significant abnormal electrocardiogram (ECG) findings including:
a. Evidence of second- or third-degree atrioventricular block.
b. Clinically significant arrhythmia (as determined by the Investigator).
c. QTc interval of > 470 msec, as calculated according to Fridericia’s formula.
- Received other recent antitumor therapy, including:
a. Investigational antitumor treatment:
• Phase 1 Dose escalation: Administered within 28 days or 5 half-lives (whichever is shorter) prior to first dose of study treatment.
• Phase 2 Dose expansion: Prior investigational systemic antitumor treatments including, but not limited to, investigational targeted therapies for 3rd generation EGFR TKI resistance
b. Phase 2 Dose expansion: Received more than 1 EGFR TKI therapy (ie, erlotinib or gefitinib) for the treatment of metastatic or recurrent EGFR NSCLC
c. Carmustine (ie, BCNU) or lomustine (ie, CCNU) in the 6 weeks prior to receiving the first dose of study treatment.
d. Temozolomide in the 23 days prior to receiving the first dose of study treatment.
e. Any standard chemotherapy or targeted therapy (including anti-neoplastic and anti-angiogenesis antibodies), within 21 days or 5 half-lives (whichever is shorter) prior to first dose of study treatment.
f. Any immune checkpoint inhibitor within 28 days prior to the first dose of study treatment.
g. Radiation therapy within 21 days prior to first dose of study treatment or limited field palliative radiation therapy within 7 days of prior to first dose of study treatment.
Major surgery within 4 weeks before first dose of study drug or scheduled for surgery during projected course of the study.
Known concurrent malignancy that is expected to require active treatment within 2 years and that may interfere with the interpretation of the efficacy and safety outcomes of the study in the opinion of the treating Investigator confirmed by the Medical Monitor.
Note: Prior malignancy that is at a low risk of progression or recurrence (eg, superficial bladder cancer, non-melanoma skin cancers, or low-grade prostate cancer not requiring therapy) is allowed.
Known active hepatitis B or C infection and/or known human immunodeficiency virus (HIV) carrier.
Poorly controlled gastrointestinal disorders that may interfere with absorption of the study drug including delayed gastric emptying, ulcerative colitis or Crohn’s disease that requires steroid therapy at any dose, refractory nausea, and vomiting, and/or prior surgical procedures affecting absorption or requirement of intravenous alimentation.
Taking or unable to discontinue proton pump inhibitors (including potassium competitive acid blockers) within 1 week prior to baseline.
Taking medications or herbal supplements that are known potent CYP3A4 or CYP2C8 inhibitors/inducers (including St. John’s wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], clopidogrel, gemfibrozil, rifampicin, yohimbe, saw palmetto, ginseng, and double-strength grapefruit juice) within 14 days before the start of treatment.
a. Patients taking anti-epileptic drugs or on enzyme-inducing anti-epileptic drugs (EIAED) that are strong or moderate inducers/inhibitors of CYP3A4 or CYP2C8 (eg, carbamazepine, phenobarbital, phenytoin, valproic acid). Patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of BDTX-1535. Note: Levetiracetam or other antiepileptic drugs that are not moderate or strong inducers or inhibitors of CYP2C8 and CYP3A4 are allowed.
Narrow therapeutic index substrates of BCRP and P-gp (eg, digoxin) (Appendix D)
Taking medications that are known risk to cause torsades de pointes within 14 days before the start of treatment.
Any history of a concomitant condition (eg, alcohol abuse, social, or psychiatric condition) that, in the opinion of the Investigator, would compromise the patient’s ability to comply with the study or interfere with the evaluation of the safety and efficacy of the study drug.
Women who are pregnant or breast-feeding.
Any history of interstitial lung disease related to EGFR TKI use.
