Clinical Trials

Date: 2016-12-18

Type of information: Presentation of results at a congress

phase: 1

Announcement: presentation of results at the European Society for Medical Oncology (ESMO) 2016 Congress

Company: Loxo Oncology (USA - CT)

Product: LOXO- 101 (larotrectinib - (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate)

Action mechanism: enzyme inhibitor/kinase inhibitor/TRK inhibitor. LOXO-101 is a potent, oral, selective inhibitor of tropomyosin receptor kinase (TRK) signaling molecules. The TRK family (TRKA, TRKB, and TRKC) has been implicated in diverse tumor types such as lung cancer, head and neck cancer, melanoma, colorectal cancer, sarcoma, and breast cancer. LOXO-101 was built specifically to inhibit TRK and is currently being evaluated in a Phase 1 dose escalation trial for patients with advanced solid tumors. LOXO-101 was developed in collaboration with Array BioPharma.

Disease: adult solid tumors

Therapeutic area: Cancer - Oncology

Country: USA

Trial details: This multicenter, open-label, Phase 1 study of orally administered LOXO-101 in adult subjects with advanced solid tumors that have progressed or are non responsive to available therapies and for which no standard or available curative therapy exists will be conducted in 2 parts: an initial dose escalation phase of LOXO-101 in subjects with advanced solid tumors. This will be followed by an expansion phase in solid tumor subjects with a neurotrophic tyrosine kinase receptor (NTRK) alteration. During the escalation phase, LOXO-101 will be taken once daily or twice daily. During the expansion phase, the LOXO-101 dose selected from the escalation phase will be explored in 30-60 additional subjects with an NTRK alteration. The objectives of the dose escalation phase are to determine the safety, tolerability, pharmacokinetic profile, and recommended dose of orally administered LOXO-101. The objectives of the expansion phase are to describe the preliminary anti-tumor activity of LOXO-101 in patients with NTRK alterations. (NCT02122913)

Latest news:

• • On December 18, 2016, Loxo Oncology announced updated results from its adult Phase 1 open-label, dose-escalation trial of larotrectinib (LOXO-101), a selective inhibitor of tropomyosin receptor kinase (TRK). The data were presented at the 2016 European Society for Medical Oncology (ESMO) Asia Congress in Singapore. Data from this ongoing Phase 1 trial were last reported at the American Association for Cancer Research (AACR) Annual Meeting in April 2016 . As of a November 10, 2016 data cutoff, 59 patients with refractory solid tumors had been enrolled and treated with single agent larotrectinib, including eight patients with cancers harboring TRK fusions. Seven patients with TRK fusion cancers were on study sufficiently long for an efficacy assessment, while an eighth TRK fusion patient had been recently enrolled and was not yet evaluated for response. Six of the seven efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. The seventh patient, as previously reported, demonstrated clear radiographic tumor regressions, including in the central nervous system, and remains on study, but had not met the threshold required for a RECIST response. All responders remained in response, with one patient in cycle 22, one patient in cycle 19, one patient in cycle 18, two patients in cycle 15 and one patient in cycle 11. Each cycle is 28 days, or approximately one month. Larotrectinib has been well tolerated at doses that include and exceed the recommended Phase 2 dose of 100 mg BID. A maximum tolerated dose (MTD) has not been defined. The majority of adverse events reported by the investigators have been mild to moderate. Larotrectinib is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of November 10, 2016 , 59 patients with advanced cancer had been treated at six dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID, 200 mg QD and 200 mg BID. The median age of these patients is 59 (ranging from 19-82) and the median number of prior treatments is three (ranging from 0-24). Safety Analysis: Larotrectinib has been well tolerated in the 59 patients treated, including 34 patients at a dose of 100mg BID. Adverse events reported regardless of attribution to study drug are generally consistent with those previously presented. The most common adverse events, largely Grade 1 and 2, include fatigue (37 percent), dizziness (29 percent), anemia (25 percent) and dyspnea (25 percent). No individual Grade 3 or 4 adverse events occurred in more than three patients treated at 100mg BID or more than five patients in the entire study population. The frequency of toxicities did not correlate with dose level. The MTD has not yet been defined. Efficacy Analysis: As of November 10, 2016 , eight patients with cancers harboring TRK fusions had been enrolled, representing a broad range of tumor types, namely mammary analogue secretory cancer of the salivary glands (MASC, n=3), gastrointestinal stromal tumor (n=2), soft tissue sarcoma, thyroid carcinoma and non-small cell lung cancer. Seven patients with TRK fusion cancers were on study sufficiently long for an efficacy assessment, while an eighth TRK fusion patient had been recently enrolled and was not yet evaluated for response. Six of the seven efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. A seventh patient, as previously reported, demonstrated clear radiographic tumor regressions, including in the central nervous system, and remains on study, but had not met the threshold required for a RECIST response. All responders remained in response, with one patient in cycle 22, one patient in cycle 19, one patient in cycle 18, two patients in cycle 15 and one patient in cycle 11. Each cycle is 28 days, or approximately one month.
• • On April 21, 2015, Loxo Oncology  announced the presentation of initial Phase 1a safety and pharmacokinetic data for LOXO-101, the only selective inhibitor of the TRK family of tyrosine kinase receptors in clinical development, in a poster session at the American Association for Cancer Research (AACR) 2015 Annual Meeting in Philadelphia, PA. The poster is entitled "Pharmacokinetics (PK) of LOXO-101 during the first-in-human Phase I study in patients with advanced solid tumors: Interim update."
• Key findings from the poster presentation include: As of the data cut-off for the poster, March 26, 2015, 15 patients have been enrolled across three dose cohorts: 50mg QD (n=4), 100mg QD (n=5), and 100mg BID (n=6), including one soft tissue sarcoma patient with an NTRK1 fusion enrolled on March 10, 2015. Pharmacokinetics show good systemic exposure of LOXO-101 after oral dosing, with higher exposures observed than those predicted in nonclinical studies. LOXO-101 was generally well tolerated with the most common adverse events being Grade 1 and 2 fatigue, dizziness and anemia; no study drug related serious adverse events (SAEs) have been reported; the maximum tolerated dose (MTD) has not yet been reached.
• In the second half of 2015, Loxo will provide an update on its clinical development plans for LOXO-101.
• • On May 1, 2014, Loxo Oncology announced that it has initiated a Phase 1 Study for its lead compound, LOXO-101. The Phase 1 study will evaluate the safety, pharmacokinetics and pharmacodynamics of escalating doses of LOXO-101 and, in a second stage, will also provide a preliminary assessment of anti-tumor activity in cancer patients preselected to have an alteration in genes affecting the TRKA, TRKB or TRKC proteins.

Is general: Yes