First-in-human Study of Oral TP-0903 (a Novel Inhibitor of AXL Kinase) in Patients With Advanced Solid Tumors

NCT02729298 | Completed Phase 1

• 1 other identifier: TP-0903-101
• Study Type: interventional
• Target: 177
• Locations: 1 country
• Sites: 16

Brief Summary

TP-0903 is a novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers. Preclinical studies have shown promising antitumor activity of TP-0903 as a single agent against a variety of tumor types in both in vitro and in vivo studies. This first-in-human Phase 1a study is conducted to identify the maximum tolerated dose (MTD) of TP-0903 administered orally to patients with advanced solid tumors and to identify the safety profile and Recommended Phase 2 Dose (RP2D) of TP-0903. Once the MTD has been established, additional patients with specific tumor types (advanced solid tumors that have progressed after achieving a best documented response of at least stable disease (ie, SD, PR, or CR documented per iRECIST following at least 2 cycles (8 weeks) of immunotherapy, EGFR+ Non Small Cell Lung Cancer \[NSCLC\] and have demonstrated recent progression following a best documented response of at least stable disease (ie, SD, PR, or CR documented per RECIST v1.1 on ≤2 lines of oral TKIs (Prior chemotherapy ± immunotherapy is allowed as long as the patient is clearly demonstrating current progression on an EGFR TKI.), BRAF-, KRAS-, or NRAS-mutated Colorectal Carcinoma \[CRC\] for whom there is no standard therapy remaining, persistent/recurrent Ovarian Cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy, and BRAF-mutated Melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor) will be enrolled at the MTD in the Phase 1b study. Data collected from patients enrolled in each of these additional cohorts will be used for to confirm safety, explore potential biomarkers, and evaluate potential signals of activity when TP-0903 is administered to specific groups of heavily pretreated patients or given in combination with immunotherapy or a tyrosine kinase inhibitor (TKI). The study will investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity profiles.

Conditions

Advanced Solid Tumors; EGFR Positive Non-small Cell Lung Cancer; Colorectal Carcinoma; Recurrent Ovarian Carcinoma; BRAF-Mutated Melanoma

Keywords

Tolero; Phase 1a / 1b; First in human; Solid Tumors with immunotherapy progression; AXL inhibitor; Advanced Malignancy; Cancer; EGFR+ NSCLC with progression on ≤2 lines of oral TKIs; BRAF-Mutated CRC; KRAS-Mutated CRC; NRAS-Mutated CRC; Persistent/Recurrent Ovarian Cancer; BRAF-Mutated Melanoma with immunotherapy progression

Outcome Measures

Primary Outcomes (1)

• Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events

  A DLT is defined as any one of the following events observed within Cycle 1: Grade 3 or greater febrile neutropenia, Grade 4 ANC for 7 or greater consecutive days, Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant bleeding or that requires a platelet transfusion, Grade 3 or 4 non-hematologic AEs including nausea, vomiting, diarrhea, and electrolyte imbalances persisting for more than 48 hours despite optimal medical management, dosing delays of 2 weeks or greater due to treatment emergent adverse events or related severe laboratory test values

  Cycle 1 (Day 1 through Day 28)

Secondary Outcomes (5)

• Area under the plasma concentration-time curve from zero to infinity [AUC(0-inf)] of oral TP-0903

  Cycles 1 and 2 (Day 1 through 23)

• Area under the plasma concentration-time curve from zero to last measured time point [AUC(0-last)] of oral TP-0903

  Cycles 1 and 2 (Day 1 through 23)

• Peak plasma concentration (Cmax) of oral TP-0903

  Cycles 1 and 2 (Day 1 through 23)

• Activity of TP-0903 on predictive biomarkers

  End of every cycle (each cycle is 28 days) and End of Study (within 14 days of the last dose of study drug or within 14 days of the decision to discontinue study treatment)

• Objective response rate using RECIST v1.1 and iRECIST

  End of every cycle (each cycle is 28 days) and End of Study (within 14 days of the last dose of study drug or within 14 days of the decision to discontinue study treatment)

Study Arms (5)

Advanced Solid Tumors

EXPERIMENTAL

Phase 1a Single daily dose of TP-0903 by oral administration on Days 1-21 of a 28 day cycle AND Phase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.

Drug: TP-0903

EGFR+ NSCLC

EXPERIMENTAL

Phase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.

Drug: TP-0903

BRAF-, KRAS-, or NRAS-Mutated CRC

EXPERIMENTAL

Phase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.

Drug: TP-0903

Persistent/Recurrent Ovarian Cancer

EXPERIMENTAL

Phase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.

Drug: TP-0903

BRAF-Mutated Melanoma

EXPERIMENTAL

Phase 1b - Upon confirmation of MTD, will receive single oral daily doses of a flat dose of TP-0903 based on the average of the dose administered in the MTD expansion safety cohort on Days 1-21 of each 28 day cycle.

Drug: TP-0903

Interventions

TP-0903 DRUG

Novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers

Advanced Solid Tumors; BRAF-, KRAS-, or NRAS-Mutated CRC; BRAF-Mutated Melanoma; EGFR+ NSCLC; Persistent/Recurrent Ovarian Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients enrolled in the Phase 1a study must:
• Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor
• Be refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition
• Patients enrolled in the Phase 1b study must meet criteria for one of the following tumor types:
• Have tumors that have progressed after achieving a best documented response of at least stable disease (ie, SD, PR, or CR documented per iRECIST following at least 2 cycles (8 weeks) of immunotherapy and are felt to be appropriate for this type of treatment\*
• Have EGFR+ NSCLC and have demonstrated recent progression following a best documented response of at least stable disease (ie, SD, PR, or CR documented per per RECIST v1.1 on ≤2 lines of oral TKIs and are felt to be appropriate for this type of treatment\* Prior chemotherapy ± immunotherapy is allowed as long as the patient is clearly demonstrating current progression on an EGFR TKI.
• Have BRAF-, KRAS-, or NRAS-mutated CRC for whom there is no standard therapy remaining
• Have persistent/recurrent ovarian cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy
• Have BRAF-mutated melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor
• Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1 or iRECIST
• Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization \[WHO\]) performance of ≤1
• Have a life expectancy ≥3 months
• Be ≥18 years of age
• Have a negative pregnancy test (if female of childbearing potential)
• Have acceptable liver function:

You may not qualify if:

• Have New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial infarction within the past 6 months prior to Day 1, unstable arrhythmia, or evidence of ischemia on electrocardiogram (ECG) or during Cardiac Stress Testing within 14 days prior to Day 1 (Appendix C)
• Have a corrected QT interval (QTcF, Fridericia's method) of \>450 msec in men and \>470 msec in women
• Have a seizure disorders requiring anticonvulsant therapy
• Presence of symptomatic central nervous system metastatic disease or disease that requires local therapy such as radiotherapy, surgery, or increasing dose of steroids within 2 weeks prior to Day 1
• Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of ≤88% breathing room air)
• Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to Day 1
• Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
• Are pregnant or nursing
• Received treatment with radiation therapy, surgery, chemotherapy, or investigational therapy within 28 days or 5 half lives, whichever occurs first, prior to study entry (6 weeks for nitrosoureas or Mitomycin C)
• Are unwilling or unable to comply with procedures required in this protocol
• Have known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C. Patients with history of chronic hepatitis that is currently not active are eligible
• Have a serious nonmalignant disease (eg, hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor
• Are currently receiving any other investigational agent
• Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation
• Have undergone significant surgery to the gastrointestinal tract that could impair absorption or that could result in short bowel syndrome with diarrhea due to malabsorption

Sponsors & Collaborators

• Sumitomo Pharma America, Inc.: lead

Study Sites (16)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

HonorHealth Research Institute

Scottsdale, Arizona, 85258, United States

Location

University of Colorado Denver

Denver, Colorado, 80045, United States

Location

US Oncology - Rocky Mountain Cancer Centers, LLP (RMCC)

Denver, Colorado, 80218, United States

Location

Mayo Clinic Florida

Jacksonville, Florida, 32224, United States

Location

Miami Cancer Institute

Miami, Florida, 33176, United States

Location

University of Kansas Cancer Center

Fairway, Kansas, 66205, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55905, United States

Location

US Oncology - Willamette Valley Cancer Institute and Research Center

Eugene, Oregon, 97401, United States

Location

US Oncology - Texas Oncology Austin

Austin, Texas, 78705, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

US Oncology - Texas Oncology - Fort Worth

Fort Worth, Texas, 76104, United States

Location

University of Texas Science Center at San Antonio (UTHSCSA)

San Antonio, Texas, 78229, United States

Location

US Oncology - Texas Oncology - Tyler

Tyler, Texas, 75702, United States

Location

US Oncology - Virginia Cancer Specialists (VCS)

Fairfax, Virginia, 22031, United States

Location

Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Ovarian Neoplasms; Neoplasms

Interventions

dubermatinib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Stephen P Anthony, DO

  Sumitomo Pharma America, Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 28, 2016
• First Posted: April 6, 2016
• Study Start: December 14, 2016
• Primary Completion: June 29, 2022
• Study Completion: June 29, 2022
• Last Updated: November 14, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (16)