A Study of Subjects with NSCLC with c-Met EXON 14 Skip Mutations and c-Met Dysregulation Advanced Solid Tumors

Overview

About this study

This is a Phase 1 / 2 open-label study to assess the safety and tolerability of APL-101, to determine the RP2D and dose limiting toxicities for APL-101, and to obtain preliminary efficacy in subjects
with c-Met dysregulation in advanced malignancies and Non-Small Cell Lung Cancer (NSCLC). c-Met dysregulation will be determined by local/archival molecular pre-screening evaluations for eligibility of enrollment.
Mayo Clinic will be participating in both Part A (Phase 1) & (Phase 2) B of the study.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria: 

  • Able to understand and comply with the study procedures, understand the risks involved in the study, and provide written informed consent before any study-specific procedure is performed.
  • Men and women 18 years of age or older.
  • For Phase 1, histologically and / or cytological confirmed unresectable or metastatic solid malignancy, refractory to standard therapies with no more than three prior lines of therapy. 
  • For Phase 2, five cohorts will be enrolled:
  • Cohort A-1: NSCLC EXON 14 skip mutation (c-Met naïve) for first line treatment.
  • Cohort A-2: NSCLC EXON 14 skip mutation (c-Met naïve) pretreated subjects with no more than 3 lines of prior therapy in the metastatic setting.
  • Cohort B: NSCLC EXON 14 skip mutation (c-Met experienced; radiographic progression on prior c-Met inhibitor).
  • Cohort C: basket of tumor types with c-Met high level amplification (NSCLC EXON 14 skip mutation excluded).
  • Cohort D: basket of tumor type with c-Met fusions.
  • Cohort A-1: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor naïve
    • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations as determined by MI Transcriptome™ companion diagnostic (CDx) by central laboratory, Caris Life Sciences;
    • All histologies, including pulmonary sarcomatoid carcinoma and squamous
    • Unresectable or metastatic disease (Stage 3b/4);
    • Treatment naïve subjects in first line;
    • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
  • Cohort A-2: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor naïve (≥ 2L)
    • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations;
    • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
    • Unresectable or metastatic disease (Stage 3b/4);
    • Pretreated subjects refractory to or intolerable to standard therapies (if available, must include anti-PD-1/PD-L1 based systemic therapy) with no more than three lines of prior therapy in the metastatic setting ;
    • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
  • Cohort B: EXON 14 Non-Small-Cell Lung Cancer – c-Met inhibitor experienced
    • Histologically or cytologically confirmed NSCLC with EXON 14 skip mutations; 
    • All histologies, including pulmonary sarcomatoid carcinoma and squamous;
    •  Unresectable or metastatic disease (Stage 3b/4);
    •  Refractory to standard therapies with no more than three prior lines of therapy in the metastatic setting;
    • Radiographic progression on any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.) at any point in the past 4c.
  • Cohort C: Basket Tumor Types (c-Met high-level amplifications):
    • Any tumor type regardless of histology, including osimertinib relapsed/refractory NSCLC, excluding NSCLC EXON 14 skip mutation, that meets inclusion criteria c-Met high-level amplification;
    • Unresectable or metastatic disease, refractory to standard therapies with no more than three prior lines of therapy in the metastatic setting;
    • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
  • Cohort D: Basket Tumor Types (c-Met fusions)
    • Any other tumor type histology that meets inclusion criteria c-Met fusions;
    • Unresectable or metastatic disease, refractory to standard therapies with no more than three prior lines of therapy in the metastatic setting;
    • Not received any c-Met inhibitor (e.g., crizotinib, capmatinib, savolitinib, etc.).
  • Abnormal c-Met dysregulation, by tissue and/or plasma, defined as the following from archival/local results or molecular pre-screening evaluations. 
  • Phase 1 (100, 200, and 300 mg Cohorts)
    • c-Met overexpression by IHC 2+ ≥ 50% of tumor cells; 
    • or c-Met amplification (c-Met/Cep-7 ratio ≥ 2.2 or GCN ≥ 6 gene copy);
    • or c-Met EXON 14 skip mutation per NGS or RT-PCR;
    • or c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34- MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1- MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1- MET; KIF5B-MET and any other known c-Met activating mutations.
  • Phase 1 (400 mg Cohort) and Phase 2 RP2D
    • c-Met high-level amplification (c-Met/Cep-7 ratio of ≥ 2.2 or GCN of ≥ 6 copy). A minimum of five subjects of the high-level amplification (c-Met/Cep-7 ratio of ≥ 5 or GCN ≥ 10 gene copy) for the Stage 1 of the Simon 2 stage design is required);
    • or c-Met EXON 14 skip mutation per NGS;
    • or c-Met fusions including the following, but not limited to: BAIAP2L1-MET; C8orf34- MET; CAPZA2-MET; DCTN1-MET; EPS15-MET; LRRFIP1-MET; MET-MET; OXR1- MET; PPFIBP1-MET; PTPRZ1-MET; TFG-MET; TPR-MET; TRIM4-MET; ZKSCAN1- MET; KIF5B-MET;
    • or other c-Met mutations in Dose Escalation (400 mg Cohort).
  • Local/archival result of a positive c-Met dysregulation is required. In Phase 2, Cohorts A-2 and D require provision of tumor tissue samples (archival or fresh tumor biopsy). For Cohorts B and C, provision of tumor tissue (archival or fresh tumor biopsy) or plasma sample for entry is acceptable.
  • Across Phase 2 five cohorts, treated or untreated asymptomatic parenchymal CNS disease or leptomeningeal disease is allowed. 
  • Measurable disease according to RECIST v1.1. (or relevant criteria per tumor type).
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0–1.
    • Acceptable organ function, as evidenced by the following laboratory data during Screening period: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN;
    • Total serum bilirubin ≤ 1.5 x ULN ;
    • For subjects with liver metastases: Total bilirubin ≤ 3.0 x ULN, AST/ ALT ≤ 5 x ULN;
    • Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3 (1.5 x 10^9 /L); 
    • Platelet count ≥ 100,000 cells/mm^3 (100 x 10^9 /L);
    • Serum creatinine levels ≤ 1.5 ULN or Creatinine Clearance (CrCl) ≥ 60 mL/min as calculated by the Cockcroft-Gault method;
    • Hemoglobin ≥ 9 g/dL.
  • For all prior anticancer treatment, including radiotherapy, chemotherapy, or targeted agents or hormonal therapy, a duration of 30 days or 5 half-lives of the agents used, whichever is shorter, must have elapsed, and any encountered toxicity must have resolved to levels meeting all the other eligibility criteria prior to the first dose of study treatment. 
  • Adequate cardiac function (≤ NYHA class II) or normal cardiac function with left ventricular ejection fraction (LVEF) ≥ 50% at screening.
  • Women of child-bearing potential (WOCBP) must have a negative serum or β-human chorionic gonadotropin (β-hCG) at screening or evidence of surgical sterility or evidence of postmenopausal status. Post-menopausal status is defined as any of the following: natural menopause with menses > 1 year ago; radiation or chemotherapy inducted oophorectomy with menses > 1 year ago and follicle stimulating hormone (FSH) level in the menopausal range.
  • All subjects with reproductive potential must agree, and site must document as such, the use of effective contraceptive measures (e.g., oral contraceptives, intrauterine device, or double barrier method of condom and spermicide) during the study and for 7 months (WOCBP) or 4 months (men) following the last dose of study drug.
    • Notes: A postmenopausal woman will be defined as having no menses for 12 months without an alternative medical cause. Male sterility will be defined as only men sterilized surgically. For male subjects with a pregnant partner, a condom should be used for contraception. For male subjects with a non-pregnant female partner of child-bearing potential and woman of childbearing potential one of the following birth control methods with a failure rate of less than 1% per year when used consistently and correctly are recommended:
    • Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation given orally, intravaginally, or transdermally;
    • Progesterone-only hormonal contraception associated with inhibition of ovulation given orally, by injection, or by implant;
    • Intrauterine device (IUD);
    • Intrauterine hormone-releasing system (IUS);
    • Bilateral tubal occlusion;
    • Vasectomized partner;
    • Sexual abstinence - Birth control methods unacceptable for this clinical trial are: a. Periodic abstinence (calendar, symptothermal, or post-ovulation methods);
    • Withdrawal (coitus interruptus); 
    • Spermicide only d. Lactational amenorrhea method. 
  • Resolution of all acute chemotherapy, radiotherapy or surgery-related AEs to Grade ≤ 1, except for alopecia.
  • No planned major surgery within 4 weeks of first dose of APL-101.
  • Willing and able to participate in all required evaluations and procedures in this study including swallowing APL-101 in accordance administration schedule outlined.

Exclusion Criteria:

  • Hypersensitivity to APL-101, excipients of the drug product, or other components of the study treatment regimen.
  • Known mutation/gene rearrangement of EGFR (except for Cohort C), ALK, ROS1, RET, NTRK, KRAS, and BRAF.
  • Use or intended use of any other investigational product, including herbal medications, through Study Treatment Termination.
  • Active uncontrolled systemic bacterial, viral, or fungal infection or clinically significant, active disease process, which in the opinion of the investigator makes the risk:benefit unfavorable for the participation of the trial. Screening for chronic conditions is not required.
  • Life-threatening illness, significant organ system dysfunction or comorbid conditions, or other reasons that, in the investigator’s opinion, could compromise the subject’s safety or the integrity of the study outcomes, or interfere with the absorption or metabolism of APL-101.
  • Unstable angina or myocardial infarction within 1 year prior to first dose of APL-101, symptomatic or unstable arrhythmia requiring medical therapy, history of congenital prolonged QT syndrome, prolonged QT interval correctd by Fridericia formula (QTcF) at screening (> 450 msec based on the average of 3 measurements), or concurrent treatment with a medication that is a known risk for prolonging the QT interval. Chronic controlled atrial fibrillation is not excluded.
  • Historical seropositive results consistent with active infection for hepatitis C virus (HCV) or hepatitis B virus (HBV) with high viral loads not actively managed with antiviral therapy and human immunodeficiency virus (HIV) positive patients who are not clinically stable or on). If history is unclear, a test at Screening will be required.
  • Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments.
  • Unable to swallow orally administered medication whole.
  • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g., Crohn’s, ulcerative colitis, active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
  • Women who are breastfeeding.
  • Subjects with complications from prior radiation therapy will not be eligible until AEs return to baseline or ≤ Grade 1.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Jacksonville, Fla.

Mayo Clinic principal investigator

Kabir Mody, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Rochester, Minn.

Mayo Clinic principal investigator

Sani Kizilbash, M.D., M.P.H.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Mahesh Seetharam, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

Publications are currently not available

Study Results Summary

Not yet available

Supplemental Study Information

Not yet available

Additional contact information

Cancer-related trials contact form

Phone: 855-776-0015 (toll-free)

International patient clinical studies questions