Advanced Solid Tumor, Medullary Thyroid Cancer, Metastatic Solid Tumor, Non Small Cell Lung Cancer, RET Gene Mutation
Conditions
Keywords
Non small cell lung cancer, Non-small cell lung cancer, NSCLC, Medullary Thyroid Cancer, MTC, RET gene mutation, RET gene alteration, Advanced non small cell lung cancer, Advanced/metastatic disease, lung cancer, lung adenocarcinoma, Metastatic solid tumor, Advanced Solid Tumors, RET gene fusion, RET inhibitor, SRC, TPX-0046, Thyroid cancer
Brief summary
A phase 1/2, first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of the novel RET/SRC inhibitor TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring RET mutations or alterations. The study consists of three portions: 1) Phase 1 Dose Escalation and Food Effect Sub-study, and 2) Phase 1 dose expansion and 3) Phase 2 efficacy evaluation.
Detailed description
Phase 1 Dose Escalation and Dose Expansion: To evaluate the overall safety profile, characterize the PK profiles and assess the preliminary efficacy of TPX-0046 in adults subjects with advanced solid tumors harboring oncogenic RET fusions or mutations. Food Effect Sub-Study: To determine the effect of food on PK of TPX-0046 in adult subjects with advanced or metastatic solid tumors harboring oncogenic RET fusions or mutations. Phase 2 Efficacy Evaluation: To determine the overall safety and anti-tumor efficacy of TPX-0046 in defined cohorts of subjects with advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations.
Interventions
DRUGTPX-0046
Oral TPX-0046 capsules
Sponsors
Turning Point Therapeutics, Inc.
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
1. Age ≥ 18 (or age ≥ 20 as required by local regulation). 2. Histological or cytological confirmation of advanced/metastatic solid tumors harboring oncogenic RET fusions or mutations, who either have disease progression on, or are intolerant to standard therapy; OR are ineligible for standard therapy or for whom no standard therapy exists; OR are unlikely to tolerate or derive clinical benefit from standard therapy in the opinion of the Investigator OR have declined standard therapy. 3. ECOG performance status ≤ 1. 4. Existence of measurable or evaluable disease (according to Response evaluation criteria in solid tumors \[RECIST v1.1\] criteria). 5. Subjects with asymptomatic primary CNS tumors or brain metastases are eligible for the study if they meet protocol specified criteria. 6. Adequate organ function. 7. Life expectancy ≥ 12 weeks.
Exclusion criteria
1. Locally advanced solid tumor that is a candidate for curative treatment through radical surgery and/or radiotherapy, or chemotherapy. 2. Presence or history of any other primary malignancy within 3 years other than a history of adequately treated basal or squamous cell carcinoma of the skin, or any adequately treated in situ carcinoma. 3. Major surgery within four weeks of the start of therapy. 4. Clinically significant cardiovascular disease (either active or within six months before enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of CTCAE version 5.0 grade ≥ 2. 5. Any of the following cardiac criteria: * Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) \> 470 msec obtained from three ECGs, using the screening clinic ECG machine-derived QTc value * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec) * Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval 6. Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity). 7. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption. 8. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers. 9. Subjects with current or anticipated need for drugs that are sensitive CYP2C9 substrates with narrow therapeutic indices.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 28 days following the first highest dose of the dose regimen administered in Cycle 1 | Participants are eligible for DLT evaluation if they experience a DLT after at least one dose of TPX-0046, or do not experience a DLT after taking at least 75% of the doses expected during the DLT evaluation period. Some adverse events, graded using Common Terminology for Adverse Events (CTCAE) v. 5.0, for defining DLTs include: * Toxicities resulting in an excessive number of missed doses; * Hematologic: CTCAE grade ≥ 4 neutropenia, CTCAE grade ≥ 4 platelet count decrease, CTCAE grade ≥ 4 anemia, CTCAE grade ≥ 3 febrile neutropenia; * Renal: CTCAE grade ≥ 3 creatinine increase; * Hepatic: CTCAE grade ≥ 3 total bilirubin elevation; * Pancreatic: CTCAE grade 3 serum amylase or lipase increased with clinical symptoms or any grade ≥ serum amylase; * Cardiac: CTCAE grade ≥ 3; * Other AEs: CTCAE grade 3 vomiting or nausea that does not resolve to grade ≤ 1 within 4 days despite optimal anti-emetic therapy or any grade ≥ 4 vomiting |
| Maximum Tolerated Dose (MTD) of TPX-0046 | 28 days following the first highest dose of the dose regimen administered in Cycle 1 | The MTD is defined as the highest dose level of TPX-0046 observed to cause a dose limiting toxicity (DLT) in fewer than 33% of the treated participants in the first treatment cycle (ie, Cycle 1, 28 days). |
Countries
South Korea, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 10 mg QD TPX-0046 10 mg daily (QD) in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 4 |
| 10 mg BID TPX-0046 10 mg twice a day (BID) in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 4 |
| 20 mg QD TPX-0046 20 mg daily (QD) in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 4 |
| 30 mg QD TPX-0046 30 mg daily (QD) in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 8 |
| 20 mg BID TPX-0046 20 mg twice a day (BID) in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 3 |
| 20 mg QD to 30 mg QD TPX-0046 20 mg daily (QD) for the first 14 days, then 30 mg daily in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 3 |
| 20 mg QD to 20 mg BID TPX-0046 20 mg daily (QD) for the first 14 days, then 40 mg in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 7 |
| 20 mg QD to 40 mg QD TPX-0046 20 mg (daily) QD for the first 14 days, then 40 mg in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 6 |
| 10 mg QD to 10 mg BID TPX-0046 10 mg daily (QD) for the first 14 days, then 20 mg in 28-day continuous cycles until disease progression, unacceptable toxicity, the ability to move to alternative care is identified, or withdrawal of consent | 2 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 3 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 2 | 0 | 0 | 2 | 0 | 0 |
| Overall Study | Progressive Disease | 4 | 3 | 3 | 5 | 3 | 3 | 5 | 2 | 2 |
Baseline characteristics
| Characteristic | 20 mg QD to 40 mg QD | Total | 10 mg QD to 10 mg BID | 10 mg QD | 10 mg BID | 20 mg QD | 30 mg QD | 20 mg BID | 20 mg QD to 30 mg QD | 20 mg QD to 20 mg BID |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 60.5 Years STANDARD_DEVIATION 8.87 | 60.8 Years STANDARD_DEVIATION 10.52 | 61.5 Years STANDARD_DEVIATION 12.02 | 59.5 Years STANDARD_DEVIATION 5.97 | 58.0 Years STANDARD_DEVIATION 10.23 | 60.8 Years STANDARD_DEVIATION 3.59 | 60.1 Years STANDARD_DEVIATION 15.69 | 59.3 Years STANDARD_DEVIATION 19.5 | 64.7 Years STANDARD_DEVIATION 9.45 | 62.7 Years STANDARD_DEVIATION 10.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 34 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 7 Participants | 2 Participants | 3 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 5 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 5 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 28 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 2 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 18 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants | 0 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 23 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 3 Participants | 3 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 3 / 4 | 4 / 4 | 4 / 8 | 2 / 3 | 2 / 3 | 5 / 7 | 2 / 6 | 0 / 2 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 4 / 4 | 8 / 8 | 3 / 3 | 3 / 3 | 7 / 7 | 6 / 6 | 1 / 2 |
| serious Total, serious adverse events | 2 / 4 | 1 / 4 | 4 / 4 | 7 / 8 | 2 / 3 | 0 / 3 | 6 / 7 | 4 / 6 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of TPX-0046
The MTD is defined as the highest dose level of TPX-0046 observed to cause a dose limiting toxicity (DLT) in fewer than 33% of the treated participants in the first treatment cycle (ie, Cycle 1, 28 days).
Time frame: 28 days following the first highest dose of the dose regimen administered in Cycle 1
Population: All treated participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 10 mg QD | Maximum Tolerated Dose (MTD) of TPX-0046 | 32.54 mg |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046
Participants are eligible for DLT evaluation if they experience a DLT after at least one dose of TPX-0046, or do not experience a DLT after taking at least 75% of the doses expected during the DLT evaluation period. Some adverse events, graded using Common Terminology for Adverse Events (CTCAE) v. 5.0, for defining DLTs include: * Toxicities resulting in an excessive number of missed doses; * Hematologic: CTCAE grade ≥ 4 neutropenia, CTCAE grade ≥ 4 platelet count decrease, CTCAE grade ≥ 4 anemia, CTCAE grade ≥ 3 febrile neutropenia; * Renal: CTCAE grade ≥ 3 creatinine increase; * Hepatic: CTCAE grade ≥ 3 total bilirubin elevation; * Pancreatic: CTCAE grade 3 serum amylase or lipase increased with clinical symptoms or any grade ≥ serum amylase; * Cardiac: CTCAE grade ≥ 3; * Other AEs: CTCAE grade 3 vomiting or nausea that does not resolve to grade ≤ 1 within 4 days despite optimal anti-emetic therapy or any grade ≥ 4 vomiting
Time frame: 28 days following the first highest dose of the dose regimen administered in Cycle 1
Population: DLT evaluable participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 10 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 0 Participants |
| 10 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 0 Participants |
| 20 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 0 Participants |
| 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 2 Participants |
| 20 mg QD to 30 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 1 Participants |
| 20 mg QD to 20 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 0 Participants |
| 20 mg QD to 40 mg QD | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 2 Participants |
| 10 mg QD to 10 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 0 Participants |
| 20 mg BID | Number of Participants With Dose Limiting Toxicities (DLTs) of TPX-0046 | 0 Participants |