Larotrectinib for the Treatment of NTRK Amplification Positive, Locally Advanced or Metastatic Solid Tumors

A Phase II Basket Study of the Oral TRK Inhibitor Larotrectinib (BAY2757556) in Subjects With NTRK Amplification Positive and Pan-TRK Positive Tumors

This phase II trial studies the effect of larotrectinib in treating patients with NTRK gene amplification positive solid tumors that have spread to nearby tissues or lymph nodes (locally advanced) or other places in the body (metastatic). Larotrectinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVE:

I. To determine overall response rate (ORR) to larotrectinib sulfate (larotrectinib) in patients with advanced solid tumors harboring NTRK amplification and pan-TRK expression by immunohistochemistry (IHC), calculated as the proportion of subjects with confirmed complete (CR) or partial response (PR) as best response and as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and Response Assessment in Neuro-Oncology (RANO) criteria in primary central nervous system (CNS) tumor.

SECONDARY OBJECTIVES:

I. To evaluate the duration of response (DOR) in subjects with CR or PR as best response.

II. To estimate the proportion of subjects with any tumor regression as best response.

III. To evaluate the growth modulation index (GMI) following initiation of larotrectinib.

IV. To evaluate overall (OS) and progression-free survival (PFS) following initiation of larotrectinib.

V. To evaluate the clinical benefit rate (CBR) based on the proportion of subjects with best response of CR, PR, or stable disease lasting >= 16 weeks following initiation of larotrectinib safety.

VI. To assess the safety profile and tolerability of larotrectinib.

EXPLORATORY OBJECTIVES:

I. To characterize NTRK1, NTRK2, and NTRK3 amplification by next-generation sequencing of tumor biopsies.

II. To characterize TRKA, TRKB, and TRKC signaling in fresh pre-treatment tumor biopsies, with the aim of elucidating TRK biology and modifiers of response to larotrectinib.

III. To characterize concurrently activated oncogenic pathways in fresh pre-treatment tumor biopsies, with the aim of elucidating TRK biology and modifiers of response to larotrectinib.

OUTLINE:

Patients receive larotrectinib sulfate orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of unacceptable toxicity. Patients who experience disease progression and are deriving clinical benefit from larotrectinib may continue treatment per physician discretion.

After completion of study treatment, patients are followed up at 4 weeks, and then every 3 months for 2 years.

Inclusion Criteria:

• At least 16 years of age

• Locally-advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene amplification identified through molecular assays (such as IHC and any next-generation sequencing [NGS] platform, reference lab NGS, or in house NGS platform) as routinely performed at The University of Texas MD Anderson Cancer Center or other similarly-certified laboratories. The minimum level of amplification is 7 copies. This rationale of amplification level is based on data from MOCLIA at The University of Texas MD Anderson Cancer Center

• Must have received prior standard therapy appropriate for tumor type and stage of disease, or, in the opinion of the investigator, is unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy

• Must have at least one measurable lesion as defined by RECIST v1.1. Subjects with primary CNS tumors should meet the following criteria:

  • Must have received prior treatment including radiation and/or chemotherapy, with radiation completed > 12 weeks prior to cycle 1 day 1 (C1D1) of therapy, as recommended or appropriate for the tumor type
  • Must have >= 1 site of bi-dimensionally measurable disease (confirmed by magnetic resonance imaging [MRI] and evaluable by RANO), with the size of at least one of the measurable lesions >= 1 cm in each dimension
  • Must have imaging study within 28 days before enrollment. If on steroid therapy, the dose must be stable for at least five days immediately before and during the imaging study

• Eastern Cooperative Oncology Group (ECOG) score =< 3. If enrolled with primary CNS tumor to be assessed by RANO, Karnofsky performance score (KPS) >= 70 %

• Archived tumor tissue. If archival tissue is unavailable, an on-study tumor biopsy should be attempted if it can be safely performed

• Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) < 2.5 x upper limit of normal (ULN) or < 5 x ULN if liver function abnormalities are due to underlying malignancy

• Total bilirubin < 2.5 x ULN, except in cases of biliary obstruction. Subjects with a known history of Gilberts disease and an isolated elevation of indirect bilirubin are eligible

• Serum creatinine < 2.0 x ULN or estimated glomerular filtration rate >= 30 mL/minute using the Cockcroft-Gault formula

• Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation

• Willingness of men and women of reproductive potential to use two effective birth control methods, one used by the subject and another by his/her partner, for the duration of treatment and for 3 months following study completion

Exclusion Criteria:

• Investigational agent or anticancer therapy within 2 weeks prior to the planned start of larotrectinib or five half-lives, whichever is shorter, and without clinically significant toxicities from that therapy

• Prior progression while receiving approved or investigational tyrosine kinase inhibitors targeting TRK. However, subjects who received less than 28 days of such treatment and discontinued because of intolerance or toxicity are eligible

• Symptomatic or unstable brain metastases that needs corticosteroid usage. Subjects with asymptomatic brain metastases or primary CNS tumors are eligible

• Uncontrolled concurrent malignancy that would limit assessment of efficacy. Allowed diseases may include, but are not limited to in situ cancers of cervix, breast, or skin, superficial bladder cancer, limited-stage prostate cancer, and basal or squamous cancers of the skin

• Active uncontrolled systemic bacterial, viral, or fungal infection, unstable cardiovascular disease or other systemic disease that would limit compliance with study procedures. Unstable cardiovascular disease is defined as:

  • Persistently uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg despite antihypertensive therapy
  • Myocardial infarction within 3 months of screening

• Stroke within 3 months of screening

• Inability to discontinue treatment with a strong cytochrome P450 (CYP450), 3A4 (CYP3A4) inhibitor or inducer prior to start of treatment

• Pregnancy or lactation