Details

IRB Study Number 17-582

Status Active, not recruiting

Phase Phase 1

Location Cleveland Clinic Main Campus

Institute Taussig Cancer Institute

Description

Description

Primary Objective

  • To determine the MTD/recommended dose for further study of oral LOXO-292 in patients with advanced solid tumors, including RET-fusion NSCLC, MTC, and other tumors with increased RET activity.
    Secondary Objectives

  • To determine the safety profile and tolerability of LOXO-292, including both acute and chronic toxicities.

  • To characterize the PK properties of LOXO-292.
  • To assess, for each expansion cohort, the preliminary anti-tumor activity of LOXO-292 when administered to patients with tumors harboring abnormalities in RET, by determining:

    • Overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO), as appropriate to tumor type;
    • Duration of response (DOR) in patients with best overall response of complete response (CR) or partial response (PR);
    • Best change in tumor size from baseline;
    • Clinical benefit rate (CBR) based on the proportion of patients with best overall response of CR, PR or stable disease (SD) lasting 6 or more months following initiation of treatment with LOXO-292;
    • Duration of progression-free survival (PFS) following initiation of LOXO-292
    • Duration of overall survival (OS) following initiation of LOXO-292.
      Exploratory Objectives
  • To determine the relationship between PK and drug effects, including efficacy and safety.

  • To evaluate the serum tumor markers carcinoembryonic antigen (CEA) and calcitonin before, during, and at the end of treatment with LOXO-292 (for patients with MTC only).
  • To characterize RET gene fusions and mutations by molecular analysis, including next-generation sequencing (NGS) from tumor biopsies and circulating tumor DNA.
  • To characterize concurrently activated oncogenic pathways in pre-treatment tumor biopsies with the aim of elucidating RET biology, and modifiers of response to LOXO-292.
  • To assess changes in tumor molecular status in fresh tumor biopsies and circulating tumor DNA obtained during treatment and after progression on LOXO-292, with the aim of elucidating RET biology, modifiers of response, and mechanisms of acquired resistance to LOXO-292

Inclusion Criteria

Inclusion Criteria

Dose Escalation 1. Adult patients with a locally advanced or metastatic solid tumor refractory to standard of care therapy, or for whom no standard of care therapy is available, or who in the opinion of the Investigator, is not a candidate for, or, would be unlikely to tolerate or derive significant clinical benefit from standard of care therapy. 2. Any number of prior TKIs with anti-RET activity are allowed. Refer to Appendix A for examples of MKIs with anti-RET activity. The specific agent(s), duration of treatment, clinical benefit and reason for discontinuation (e.g., PD, drug toxicity or intolerance) should be documented for all kinase inhibitors the patient has been exposed to. 3. Evidence of a RET gene alteration in tumor and/or blood (e.g., gene rearrangement and/or mutation, excluding synonymous, frameshift or nonsense mutations), determined with prior molecular assays as performed in a CLIA-certified or equivalent laboratory. 4. Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type. 5. At least 18 years of age. 6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 with no sudden deterioration 2 weeks prior to the first dose of study treatment. 7. Life expectancy of at least 3 months. 8. Archived tumor tissue sample available or lesion that can be safely biopsied if the archived sample is not available. 9. Adequate hematologic status, (see protocol). 10. Adequate hepatic function, (see protocol). 11. Serum calcium level between 8.0 mg/dL and the institutional ULN. 12. Serum thyroid stimulating hormone (TSH) level ≤10 U/mL. 13. Adequate renal function, with estimated glomerular filtration rate ≥30 mL/minute. 14. Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. 15. Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.

Dose Expansion 1. Adult patients with a locally advanced or metastatic solid tumor with evidence of a RET gene alteration in tumor and/or blood (e.g., gene rearrangement and/or mutation, excluding synonymous, frameshift and nonsense mutations), as determined with prior molecular assays as performed in a CLIA-certified or equivalent laboratory. 2. For MTC: have PD within the previous 14 months as defined by RECIST 1.1. 3. Any number of prior TKIs with anti-RET activity are allowed. Refer to Appendix A for examples of MKIs with anti-RET activity. The specific agent(s), duration of treatment, clinical benefit and reason for discontinuation (e.g., PD, drug toxicity or intolerance) should be documented for all kinase inhibitors the patient has been exposed to. 4. At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type, not previously irradiated and not chosen for biopsy during the screening period. Patients without RECIST 1.1 or RANO measurable disease will be eligible for enrollment to Cohort 5. 5. At least 18 years of age. 6. ECOG performance status score of 0, 1, or 2 with no sudden deterioration 2 weeks prior to the first dose of study treatment. 7. Life expectancy of at least 3 months. 8. Archived tumor tissue sample available or lesion that can be safely biopsied if the archived sample is not available. 9. Adequate hematologic status, (see protocol). 10. Adequate hepatic function, (see protocol). 11. Serum calcium level between 8.0 mg/dL and the institutional ULN. 12. Serum TSH level ≤10 U/mL. 13. Adequate renal function, with estimated glomerular filtration rate ≥30 mL/minute. 14. Ability to swallow capsules and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. 15. Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.

Exclusion Criteria

Exclusion Criteria

  1. For NSCLC patients, a targetable mutation in EGFR, or targetable rearrangement involving ALK or ROS1.
  2. Investigational agent or anticancer therapy within 2 weeks (14 days) prior to planned start of LOXO-292. In addition, no concurrent investigational therapy is permitted.
  3. Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292.
  4. Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment.
  5. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
  6. Symptomatic primary central nervous system (CNS) tumor or metastases; symptomatic leptomeningeal carcinomatosis; untreated spinal cord compression. Exception: Patients with CNS primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 14 days prior to the first dose of LOXO-292, there has been no increase in steroid dose for 14 days prior to the first dose of LOXO-292 to manage CNS symptoms, and no CNS surgery or radiation has been performed for 28 days (14 days after last radiation with stereotactic radiosurgery [SRS]).
  7. For MTC patients, clinically significant involvement in the trachea, esophagus or complete encasement of great vessels (e.g., aorta or pulmonary artery) that in the opinion of the Investigator, could result in life-threatening complications due to rapid tumor regression.
  8. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 or prolongation of the QT interval corrected for heart rate (QTcF) interval >470 msec on at least 2/3 consecutive ECGs and mean QTcF from all 3 ECGs >470 msec during Screening. Correction of suspected drug-induced QTcF prolongation may be attempted at the Investigator's discretion if clinically safe to do so.
  9. Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator makes it undesirable for the patient to participate in the trial. Screening for chronic conditions is not required.
  10. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study agent.
  11. Current treatment with certain strong CYP3A4 inhibitors or inducers (refer to Appendix C of the Protocol).
  12. Current treatment with proton pump inhibitors (PPIs) (refer to Appendix F).
  13. Pregnancy or lactation.