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Phase 1 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET-Fusion Lung Cancer and Medullary Thyroid Cancer

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ClinicalTrials.gov Identifier: NCT03157128
Recruitment Status : Recruiting
First Posted : May 17, 2017
Last Update Posted : June 5, 2018
Sponsor:
Information provided by (Responsible Party):
Loxo Oncology, Inc.

May 9, 2017
May 17, 2017
June 5, 2018
May 9, 2017
August 2019   (Final data collection date for primary outcome measure)
  • Maximum tolerated dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]
  • Recommended dose for further study [ Time Frame: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the patient discontinues from the study) ]
Maximum tolerated dose (MTD) [ Time Frame: The first 28 days of treatment (Cycle 1) ]
Complete list of historical versions of study NCT03157128 on ClinicalTrials.gov Archive Site
  • Number of participants with adverse events as assessed by CTCAE v4.03 [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of participants with serious adverse events [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in clinical laboratory results compared to baseline [ Time Frame: Day 1, 8 & 15 of Cycle 1, every 28 days starting at Cycle 2, and Day 1 & 8 after Intra-patient Dose Escalation (dose escalation only) for 24 months (or earlier if patient discontinues from the study), & through Safety Follow-up (28 days after last dose) ]
  • Number of patients with changes upon physical examination compared to baseline [ Time Frame: Day 1, 8 & 15 of Cycle 1, every 28 days starting at Cycle 2, and Day 1 & 8 after Intra-patient Dose Escalation (dose escalation only) for 24 months (or earlier if patient discontinues from the study), & through Safety Follow-up (28 days after last dose) ]
  • Number of patients with changes in vital signs compared to baseline [ Time Frame: Day 1, 8 & 15 of Cycle 1, every 28 days starting at Cycle 2, and Day 1 & 8 after Intrapatient Dose Escalation (dose escalation only) for 24 months (or earlier if patient discontinues study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in ECGs compared to baseline [ Time Frame: Day 1 & 8 of Cycle 1, every 28 days starting at Cycle 2, and Day 1 & 8 after Intra-patient Dose Escalation (dose escalation only) for ~6 months (or longer if clinically indicated), and through Safety Follow-up (28 days after the last dose) ]
  • Area under the plasma concentration time curve from 0 to 24 hours (AUC0-24) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycles 3 and 5, and Day 8 after Intra-patient Dose Escalation (dose escalation only) ]
  • Maximum plasma concentration (Cmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycles 3 and 5, and Day 8 after Intra-patient Dose Escalation (dose escalation only) ]
  • Time to maximum plasma concentration (Tmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycles 3 and 5, and Day 8 after Intra-patient Dose Escalation (dose escalation only) ]
  • Terminal half-life (t1/2) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycles 3 and 5, and Day 8 after Intra-patient Dose Escalation (dose escalation only) ]
  • Degree of Accumulation of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1, Day 1 of Cycles 3 and 5, and Day 8 after Intra-patient Dose Escalation (dose escalation only) ]
  • Overall response rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed. ]
    As assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Duration of reponse [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
    In patients with best overall response of complete response or partial response, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Best change in tumor size from baseline [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  • Clinical benefit rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
    Proportion of patients with complete response, partial response, or stable disease for at least 6 months while on LOXO-292, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Median duration of progression-free survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
  • Median overall survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
  • Recommended dose for further study [ Time Frame: The first 28 days of treatment (Cycle 1) and every cycle (28 days) for approximately 12 months (or earlier if the patient discontinues from the study) ]
  • Number of participants with adverse events as assessed by CTCAE v4.03 [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of participants with serious adverse events [ Time Frame: From the time of informed consent, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in clinical laboratory results compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes upon physical examination compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in vital signs compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Number of patients with changes in ECGs compared to baseline [ Time Frame: Day 1 (baseline) , Day 8 and Day 15 of Cycle 1 and every cycle (28 days) beginning with Cycle 2, for approximately 24 months (or earlier if the patient discontinues from the study), and through Safety Follow-up (28 days after the last dose) ]
  • Area under the plasma concentration time curve from 0 to 24 hours (AUC0-24) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Maximum plasma concentration (Cmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Time to maximum plasma concentration (Tmax) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Terminal half-life (t1/2) of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Degree of Accumulation of LOXO-292 [ Time Frame: Days 1 and 8 of Cycle 1 and Day 1 of Cycles 3 and 5 ]
  • Overall response rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed. ]
    As assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Duration of reponse [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
    In patients with best overall response of complete response or partial response, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Best change in tumor size from baseline [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
  • Clinical benefit rate [ Time Frame: Approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed ]
    Proportion of patients with complete response, partial response, or stable disease for at least 6 months while on LOXO-292, as assessed by RECIST v1.1 or RANO, as appropriate to tumor type
  • Median duration of progression-free survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
  • Median overall survival following initiation of LOXO-292 [ Time Frame: Up to 2 years ]
  • Changes in serum tumor marker calcitonin compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 and Day 15 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • Changes in serum tumor marker CEA compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 and Day 15 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • RET gene status in DNA from tumor tissue [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1 and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • RET gene status in plasma circulating free tumor DNA (cfDNA) [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1, Day 15 of Cycle 1 , Day 1 of Cycle 2, then approximately every 8 weeks for one year, then every 12 weeks, and 7 days after last dose, for approximately 24 months (or earlier if patient discontinues from study). ]
  • Changes in serum tumor marker calcitonin compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • Changes in serum tumor marker CEA compared to baseline (medullary thyroid cancer patients) [ Time Frame: Day 1 of Cycle 1 (baseline), Day 1 of Cycle 2, then Day 1 of every odd numbered cycle starting with Cycle 3, and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • RET gene status in DNA from tumor tissue [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1 and 7 days after the last dose, for approximately 24 months (or earlier if the patient discontinues from the study) ]
  • RET gene status in plasma circulating free tumor DNA (cfDNA) [ Time Frame: Up to 28 days prior to Day 1 of Cycle 1, Day 15 of Cycle 1 , Day 1 of Cycle 2, then approximately every 8 weeks for one year, then every 12 weeks, and 7 days after last dose, for approximately 24 months (or earlier if patient discontinues from study). ]
 
Phase 1 Study of LOXO-292 in Patients With Advanced Solid Tumors, RET-Fusion Lung Cancer and Medullary Thyroid Cancer
A Phase 1 Study of Oral LOXO-292 in Patients With Advanced Solid Tumors, Including RET-Fusion Non-Small Cell Lung Cancer, Medullary Thyroid Cancer, and Other Tumors With Increased RET Activity
This is a Phase 1, open-label, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity of LOXO-292 administered orally to patients with advanced solid tumors, including RET-fusion non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and other tumors with increased RET activity.
The trial will be conducted in 2 parts: dose escalation (Part 1) and dose expansion (Part 2). During Part 1, patients with advanced NSCLC, advanced MTC or other advanced solid tumors are initially eligible if the tumor has progressed following or has not adequately responded to standard therapy, or if the patient is intolerant of, unlikely to benefit from or refuses standard therapy. During Part 2, patients with NSCLC, MTC or other advanced solid tumor that harbors a RET gene alteration or other evidence of increased RET activity are eligible.
Interventional
Phase 1
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Non-Small Cell Lung Cancer
  • Medullary Thyroid Cancer
  • Colon Cancer
  • Solid Tumor
Drug: LOXO-292
Oral LOXO-292
Experimental: LOXO-292
Dose Escalation - Multiple doses of LOXO-292 Dose Expansion - The maximum tolerated dose (MTD)/recommended dose for further study of LOXO-292 as determined during Dose Escalation
Intervention: Drug: LOXO-292
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
180
105
December 2019
August 2019   (Final data collection date for primary outcome measure)

Key Inclusion Criteria:

Diagnosis during Dose Escalation (Part 1)

  • Patients with a locally advanced or metastatic solid tumor that progressed following standard therapy, or has not adequately responded to standard therapy, or for whom no standard therapy exists, or who decline standard therapy, or in the opinion of the Investigator, is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from standard therapy.
  • Once a safe dose level is achieved that is consistent with inhibiting RET, patients must have advanced NSCLC, MTC or other advanced solid tumor with evidence of RET alteration or other evidence of increased RET activity in tumor tissue and/or blood.
  • Any number of prior TKIs.
  • Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.
  • Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.
  • Adequate hematologic, hepatic and renal function.
  • Life expectancy of at least 3 months.

Inclusion Criteria:

Diagnosis during Dose Expansion (Part 2)

  • Patients with a locally advanced or metastatic solid tumor that progressed following standard therapy, or has not adequately responded to standard therapy, or for whom no standard therapy exists, or who decline standard therapy, or in the opinion of the Investigator, is not a candidate for, or would be unlikely to tolerate or derive significant clinical benefit from standard therapy.
  • Group 1: Advanced RET-fusion NSCLC with ≥ 1 prior tyrosine kinase inhibitor (TKI) that inhibit RET
  • Group 2: Advanced RET-fusion NSCLC with no prior TKI that inhibits RET
  • Group 3: Advanced RET-mutant MTC with ≥ 1 prior TKI that inhibit RET
  • Group 4: Advanced RET-mutant MTC with no prior TKI that inhibits RET
  • Group 5: Disease not measurable, other RET-altered tumors, other RET alterations, cfDNA positive for RET alteration with tumor discordant or negative, RET mutation-negative MTC with any number of prior TKIs that inhibit RET
  • For MTC: PD within the previous 14 months as defined by RECIST 1.1.
  • Any number of prior TKIs.
  • 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 may be eligible for enrollment to Group 5.
  • ECOG score of 0, 1, or 2.
  • Adequate hematologic, hepatic and renal function.
  • Life expectancy of at least 3 months.

Key Exclusion Criteria (Dose Escalation and Dose Expansion):

  • For NSCLC patients, an additional known oncogenic driver. Examples include targetable mutation in EGFR, targetable rearrangement involving ALK, or ROS1, or KRAS (for dose expansion only). Such patients may be enrolled to Cohort 5 with prior Sponsor approval.
  • Investigational agent or anticancer therapy within 5 half-lives or 2 weeks (14 days) prior to planned start of LOXO-292. LOXO-292 may be started within less than 5 half-lives or 2 weeks of prior therapy if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
  • Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292.
  • Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292, 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.
  • Symptomatic primary CNS tumor or metastases (stable CNS tumor/metastases is allowed).
  • 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 (QTcF) > 470 msec.
  • Required treatment with certain strong CYP3A4 inhibitors or inducers.
Sexes Eligible for Study: All
12 Years and older   (Child, Adult, Older Adult)
No
Contact: Patient Advocacy 855-RET-4-292 (855-738-4292) clinicaltrials@loxooncology.com
Australia,   France,   Hong Kong,   Korea, Republic of,   Singapore,   Spain,   Switzerland,   United States
 
 
NCT03157128
LOXO-RET-17001
2017-000800-59 ( EudraCT Number )
No
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
Loxo Oncology, Inc.
Loxo Oncology, Inc.
Not Provided
Study Director: S. Michael Rothenberg, MD, PhD Loxo Oncology Medical Monitor, VP of R&D
Loxo Oncology, Inc.
March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP