A Study of LY2801653 in Advanced Cancer

Conditions

Cancer

Brief summary

Part A- The purpose of this study is to determine a safe dose of LY2801653 to be given to participants with advanced cancer and to determine any side effects that may be associated with LY2801653 in this participant population. Efficacy measures will be used to assess the activity of LY2801653. Part B- The dose determined in Part A will be used along with efficacy measures to assess the activity of LY2801653 in participants with adenocarcinoma of the colon or rectum, head and neck squamous cell carcinoma (HNSCC), uveal melanoma with liver metastasis, and cholangiocarcinoma. Part C - the objective of Part C is to determine a recommended Phase 2 dose of LY2801653 that may be safely given to participants with HNSCC when taken with standard doses of cetuximab Part D - the objective of Part D is to determine a recommended Phase 2 dose of LY2801653 that may be safely given to participants with cholangiocarcinoma when taken with a standard dose of cisplatin. Part E - the objective of Part E is to determine a recommended Phase 2 dose of LY2801653 that may be safely given to participants with cholangiocarcinoma when taken with gemcitabine plus cisplatin. Part F - the objective of Part F is to determine a recommended Phase 2 dose of LY2801653 that may be safely given to participants with gastric cancer when taken with ramucirumab.

Detailed description

Parts C and D were added to the registration in November, 2013, per protocol amendment. Parts E and F were added to the registration in February, 2015, per protocol amendment.

Aiwu Ruth He, Roger B. Cohen, Crystal S. Denlinger, Ashwin R. Sama, Ariel E. Birnbaum et al. (16 authors)

The Oncologist2019-03-0460 citations

10.1634/theoncologist.2018-0411

Abstract 2647: Merestinib (LY2801653), targeting several oncokinases including NTRK1/2/3, shows potent anti-tumor effect in colorectal cell line- and patient-derived xenograft (PDX) model bearing TPM3-NTRK1 fusion

Bruce W. Konicek, Steve M. Bray, Andrew Capen, John Calley, Kelly M. Credille et al. (16 authors)

Cancer Research2016-07-151 citations

10.1158/1538-7445.am2016-2647

Abstract 4403: Preclinical evaluation of LY2801653, an orally bioavailable small molecule oncokinase inhibitor, in cholangiocarcinoma models

S. Betty Yan, Suzane L. Um, Victoria L. Peek, Megan N. Thobe, Kelly M. Credille et al. (14 authors)

Cancer Research2014-10-012 citations

10.1158/1538-7445.am2014-4403

Abstract CT237: Interim results of a first-in-human phase 1 study of the oral MET kinase inhibitor, LY2801653, in patients with advanced cancer

Jimmy J. Hwang, Roger Cohen, Kimberly Perez, Howard Safran, Aiwu Ruth He et al. (11 authors)

Cancer Research2014-10-011 citations

10.1158/1538-7445.am2014-ct237

LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.

Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR, Shih C, Stewart JA, Stewart TR, Stout SL, Uhlik MT, Um SL, Wang Y, Wu W, Yan L, Yang WJ, Zhong B, Walgren RA.

2012-12-29124 citations

10.1007/s10637-012-9912-9

Interventions

DRUGLY2801653

LY2801653 given orally once daily during 28-day cycles. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.

DRUGCetuximab

Cetuximab given via IV infusion once weekly, 400mg/m2 for first dose and 250mg /m2 for subsequent doses. If LY2801653 treatment is stopped due to toxicity after a minimum of 4 cycles, cetuximab may be continued until disease progression. In the event cetuximab treatment is stopped, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.

DRUGCisplatin

Cisplatin given via IV infusion once a week for 2 weeks and then every 3 weeks. If the LY2801653 is terminated for LY2801653-related toxicity after a minimum of 4 cycles, cisplatin may be continued as monotherapy until progression of disease. Participants discontinuing cisplatin therapy may be allowed to continue single agent LY2801653 if they are receiving clinical benefit.

DRUGGemcitabine

Gemcitabine given via IV infusion once a week for 2 weeks and then every 3 weeks. If the LY2801653 is terminated for LY2801653-related toxicity after a minimum of 4 cycles, gemcitabine may be continued as monotherapy until progression of disease. Participants discontinuing gemcitabine therapy may be allowed to continue single agent LY2801653 if they are receiving clinical benefit.

DRUGRamucirumab

Ramucirumab given via IV infusion every 2 weeks in a 28-day treatment cycle. Treatment with ramucirumab may continue until excessive toxicity or evidence of disease progression. In the absence of disease progression, treatment with LY2801653 may continue even if ramucirumab is discontinued provided no dose limiting toxicity related to LY2801653 is present. In the event that LY2801653 is discontinued, treatment with ramucirumab may be continued if there is no dose limiting toxicity related to ramucirumab.

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Part A- Diagnosed with advanced and/or metastatic cancer during dose escalation * Part B- Diagnosed with adenocarcinoma of the colon or rectum, head and neck squamous cell carcinoma, uveal melanoma with liver with metastasis, or cholangiocarcinoma * Part C - Diagnosed with head and neck squamous cell carcinoma and have received at least one prior platinum-based systemic therapy * Part D - Diagnosed with cholangiocarcinoma and have not received more than 1 prior systemic therapy * Part E - Diagnosed with cholangiocarcinoma, either intrahepatic or extrahepatic, that is unresectable, recurrent, or metastatic. Participants must not have received prior systemic front line therapy for metastatic or resectable disease (i.e. participants may have received adjuvant gemcitabine but have not yet received gemcitabine/cisplatin for recurrent metastatic disease). Participants must be, in the opinion of the investigator, an appropriate candidate for experimental therapy. Participants should be evaluated for the need to undergo biliary drainage by stent placement prior to study participation. Participants should have adequate biliary drainage with no unresolved biliary obstruction. * Part F - Histologically- or cytologically-confirmed gastric carcinoma, including gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma (participants with adenocarcinoma of the distal esophagus are eligible if the primary tumor involves the GEJ). Participants must be ramucirumab naïve. Participants must be, in the opinion of the investigator, an appropriate candidate for experimental therapy. human epidermal growth factor receptor 2 (HER2)/neu status should be documented, if known. * Must be at least 18 years of age * Adequate hematologic, renal, and liver functions * Eastern Cooperative Oncology Group (ECOG) status of 0 or 1 * Ability to swallow capsules, with the exception of head and neck squamous cell carcinoma participants who may have study drug crushed and administered through a feeding tube

Exclusion criteria

* Have serious preexisting medical conditions that would preclude participation in the study * Have a chronic underlying infection * Have symptomatic central nervous system (CNS) malignancy or metastasis * Have current acute or chronic leukemia * Are pregnant or lactating * Have hepatocellular cancer, liver cirrhosis with a Child-Pugh stage of B or higher, or have received a liver transplant * Have a history of congestive heart failure with a New York Heart Association class greater than 2, unstable angina, recent myocardial infarction (within 6 months of study enrollment), transient ischemic attacks, stroke, or arterial or venous vascular disease * Have a QTc interval greater than 470 msec * For participants in Part B, C, D, E, and F, a tumor tissue sample is mandatory, when safe and feasible, for biomarker analysis

Design outcomes

Primary

Measure	Time frame
Recommended dose for phase 2 studies: Maximum tolerated dose	Baseline to study completion (estimated as 3 months)

Secondary

Measure	Time frame
Clinical benefit rate (CBR)	Parts B, C, D: Baseline to study completion (estimated as 3 months)
Progression free survival (PFS)	Parts B, C, D: Baseline to study completion (estimated as up to 6 months)
Duration of response	Parts B, C, D: Baseline to study completion (estimated as up to 6 months)
Number of participants with clinically significant effects	Baseline to study completion (estimated as 3 months)
Pharmacokinetics: Area under the concentration/time curve (AUC)	Cycle 1, Day 1; Cycle 2, Day 1
Number of participants with tumor response	Part A: Baseline to study completion (estimated as 3 months)
Maximum tolerated dose (MTD) of LY2801653 in combination with cetuximab for phase 2 studies in HNSCC	Baseline to study completion (estimated as 3 months)
Maximum tolerated dose (MTD) of LY2801653 in combination with cisplatin for phase 2 studies in cholangiocarcinoma	Baseline to study completion (estimated as 3 months)
Maximum tolerated dose (MTD) of LY2801653 in combination with gemcitabine plus cisplatin for phase 2 studies in cholangiocarcinoma	Baseline to study completion (estimated as 3 months)
Maximum tolerated dose (MTD) of LY2801653 in combination with ramucirumab for phase 2 studies in gastric carcinoma	Baseline to study completion (estimated as 3 months)
Pharmacokinetics: Maximum plasma concentration (Cmax)	Cycle 1, Day 1; Cycle 2, Day 1

Countries

United States

Outcome results

None listed