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

Advanced Solid Tumors Clinical Trial

Official title:

A Phase 1a / 1b, First-in-human, Open-label, Dose-escalation, Safety, Pharmacokinetic, and Pharmacodynamic Study of Oral TP-0903 Administered Daily for 21 Days to Patients With Advanced Solid Tumors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02729298
• Other study ID #: TP-0903-101
• Status: Completed
• Phase: Phase 1
• Start date: December 14, 2016
• Est. completion date: June 29, 2022

Study information

• Verified date: November 2023
• Source: Sumitomo Pharma America, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This is a phase 1a / 1b, first-in-human, open-label, dose-escalation, safety, pharmacokinetics, and pharmacodynamic study of TP-0903 administered once daily for the first 21 out of 28 days.

There are 2 phases in this study. In Phase 1a (dose escalation), sequential cohorts of three (3) patients will be treated with escalated doses until the MTD is established. In the absence of dose-limiting toxicities (DLTs), the dose will be increased using a modified Fibonacci dose escalation scheme.

Once the MTD has been established, dosing will change from BSA-dependent to a flat dose based on the average of the dose administered in the MTD expansion safety cohort. Once the MTD has been established, in Ph 1b (expansion), 5 additional cohorts of up to 20 patients each with specific tumor types (up to 100 additional patients total) may be enrolled at the MTD dose level 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). Ten patients in each of these 5 Expansion Cohorts will be required to consent to undergo pre- and post-dose tumor biopsies. All patients who undergo these biopsies will comprise the 'Biopsy Cohorts' (Phase 1b).

Patients who successfully complete a 4-week treatment cycle without evidence of significant treatment-related toxicity or progressive disease will be permitted to continue to receive treatment with the same dose and dosing schedule.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 177
• Est. completion date: June 29, 2022
• Est. primary completion date: June 29, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

To be eligible for participation in the study, patients must meet all of the following inclusion criteria:

1. Patients enrolled in the Phase 1a study must:

1. Have a histologically confirmed diagnosis of advanced metastatic or progressive solid tumor

2. Be refractory to, or intolerant of, established therapy known to provide clinical benefit for their condition

2. Patients enrolled in the Phase 1b study must meet criteria for one of the following tumor types:

1. 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*

2. 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.

3. Have BRAF-, KRAS-, or NRAS-mutated CRC for whom there is no standard therapy remaining

4. Have persistent/recurrent ovarian cancer who would be platinum refractory/ resistant and have had any number of lines of prior therapy

5. Have BRAF-mutated melanoma that has not responded to immunotherapy or a combination BRAF/MEK inhibitor

3. Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1 or iRECIST

4. Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance of =1

5. Have a life expectancy =3 months

6. Be =18 years of age

7. Have a negative pregnancy test (if female of childbearing potential)

8. Have acceptable liver function:

1. Bilirubin =1.5x upper limit of normal (ULN)

*Patients receiving immunotherapy should have a bilirubin level <3.0x ULN.

2. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and alkaline phosphatase =2.5x upper limit of normal (ULN)

• If liver metastases are present, then =5x ULN is allowed.

• Patients receiving immunotherapy should have AST and ALT levels <5.0x ULN.

9. Have acceptable renal function:

a. Calculated creatinine clearance =30 mL/min

10. Have acceptable hematologic status:

1. Granulocyte =1500 cells/mm3

2. Platelet count =100,000 (plt/mm3)

3. Hemoglobin =9 g/dL

11. Have no clinically significant abnormalities on urinalysis

12. Have acceptable coagulation status:

1. Prothrombin time (PT) within 1.5x normal limits

2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits

13. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation and for at least 30 days after the last study drug dose (see Section 4.6.3). Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

14. Have read and signed the IRB-approved informed consent form prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)

15. Patients enrolled in each of the five Expansion Cohorts must be willing to consider pre-study and on-study biopsies, if safe and medically feasible, as determined by local interventional radiology (3 to 5 core samples requested at each biopsy timepoint)

Patients meeting any one of these exclusion criteria will be prohibited from participating in this study:

1. 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)

2. Have a corrected QT interval (QTcF, Fridericia's method) of >450 msec in men and >470 msec in women

3. Have a seizure disorders requiring anticonvulsant therapy

4. 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

5. Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting O2 saturation of =88% breathing room air)

6. Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to Day 1

7. Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy

8. Are pregnant or nursing

9. 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)

a. This exclusion criterion is not applicable for patients with EGFR+ NSCLC or immunotherapy-resistant tumors who are enrolled in expansion cohorts at the MTD.

10. Are unwilling or unable to comply with procedures required in this protocol

11. 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

12. 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

13. Are currently receiving any other investigational agent

14. Have exhibited allergic reactions to a similar structural compound, biological agent, or formulation

15. 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

16. Have a history of severe adverse reaction (eg, hypersensitivity reaction, anaphylaxis) to sulfonamides

17. Patients scheduled to receive immunotherapy or TKI regimens plus TP-0903 must not be currently taking high-dose steroids (ie, physiologic dose approximately equivalent to 15 mg/day of prednisone)

Related Conditions & MeSH terms

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

Intervention

Drug:
• TP-0903
Novel oral inhibitor that targets AXL kinase and reverses the mesenchymal phenotype associated with advanced cancers

Locations

Country	Name	City	State
United States	US Oncology - Texas Oncology Austin	Austin	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Colorado Denver	Denver	Colorado
United States	US Oncology - Rocky Mountain Cancer Centers, LLP (RMCC)	Denver	Colorado
United States	US Oncology - Willamette Valley Cancer Institute and Research Center	Eugene	Oregon
United States	US Oncology - Virginia Cancer Specialists (VCS)	Fairfax	Virginia
United States	University of Kansas Cancer Center	Fairway	Kansas
United States	US Oncology - Texas Oncology - Fort Worth	Fort Worth	Texas
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	Miami Cancer Institute	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	University of Texas Science Center at San Antonio (UTHSCSA)	San Antonio	Texas
United States	HonorHealth Research Institute	Scottsdale	Arizona
United States	US Oncology - Texas Oncology - Tyler	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Sumitomo Pharma America, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Area under the plasma concentration-time curve from zero to infinity [AUC(0-inf)] of oral TP-0903	Derived PK parameters by non-compartment analysis on Cycle 1.	Cycles 1 and 2 (Day 1 through 23)
Secondary	Area under the plasma concentration-time curve from zero to last measured time point [AUC(0-last)] of oral TP-0903	Derived PK parameters by non-compartment analysis on Cycle 1	Cycles 1 and 2 (Day 1 through 23)
Secondary	Peak plasma concentration (Cmax) of oral TP-0903	Derived PK parameters by non-compartment analysis on Cycle 1.	Cycles 1 and 2 (Day 1 through 23)
Secondary	Activity of TP-0903 on predictive biomarkers	Assess biomarkers in tumor tissue, PBMCs, plasma and serum. The pharmacodynamic relationships of TP-0903 exposure with exploratory biomarkers will be quantified using the Spearman rank correlation statistic.	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)
Secondary	Objective response rate using RECIST v1.1 and iRECIST	Baseline tumor assessment will be performed at screening and repeated at Cycle 2 and every even cycle thereafter.	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)