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

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.

Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

177 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-12-14

Study Completion Date

2022-06-29

Brief Summary

Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.

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.

Related Clinical Trials

Explore similar clinical trials based on study characteristics and research focus.

First-in-human Study of Oral TP-0184 in Patients With Advanced Solid Tumors

NCT03429218

Advanced Solid Tumors

COMPLETED PHASE1

Phase 1, First-in-human Study of Oral TP-1287 in Patients with Advanced Solid Tumors

NCT03604783

Advanced Solid Tumors Sarcoma Ewing Sarcoma +2 more

TERMINATED PHASE1

Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations

NCT04161391

Non Small Cell Lung Cancer Medullary Thyroid Cancer RET Gene Mutation +2 more

TERMINATED PHASE1/PHASE2

Study of ASTX029 in Subjects With Advanced Solid Tumors

NCT03520075

Solid Tumor, Adult

COMPLETED PHASE1/PHASE2

A Study to Evaluate the Safety, Pharmacokinetics, and Activity of RO7502175 as a Single Agent and in Combination With Checkpoint Inhibitor in Participants With Locally Advanced or Metastatic Solid Tumors

NCT05581004

HCC Locally Advanced or Metastatic Solid Tumors NSCLC +9 more

RECRUITING PHASE1

Detailed Description

Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.

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.

Conditions

See the medical conditions and disease areas that this research is targeting or investigating.

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

Study Design

Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.

Allocation Method

NON_RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Intervention Type DRUG

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

Interventions

Learn about the drugs, procedures, or behavioral strategies being tested and how they are applied within this trial.

TP-0903

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

Intervention Type DRUG

Eligibility Criteria

Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.

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)

Exclusion Criteria

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)

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No