KRAS Mutation-Related Tumors, Metastatic Solid Tumor, Advanced Solid Tumor
Conditions
Keywords
KRAS, KRAS-mutant, Metastatic Solid Tumor, Advanced Solid Tumor, Advanced/metastatic disease
Brief summary
A Phase 1b/2 Study of Repotrectinib in Combination with Other Anticancer Therapies for the Treatment of Subjects with KRAS-Mutant Advanced Solid Tumors (TRIDENT-2)
Detailed description
Phase 1 Dose Escalation: To evaluate tolerability of repotrectinib at increasing dose levels in combination with other anticancer therapies for the treatment of subjects with locally advanced or metastatic KRAS-mutant solid tumors Phase 2 Efficacy Evaluation: Investigate the anti-tumor efficacy and safety of repotrectinib in combination with other anticancer therapies for the treatment of patients with locally advanced or metastatic KRAS-mutant solid tumors.
Interventions
DRUGTPX-0005
Oral TPX-0005 capsules
DRUGTrametinib
Oral trametinib tablets
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
* Age ≥ 18 (or as required by local regulation). * Histological or cytological confirmation of unresectable or metastatic solid tumor malignancy harboring a KRAS mutation. * No more than 3 prior standard treatments appropriate for tumor type and stage of disease. * ECOG performance status ≤ 1. * Existence of measurable disease (according to Response evaluation criteria in solid tumors \[RECIST v1.1\] criteria). * Subjects with asymptomatic CNS metastases and/or asymptomatic leptomeningeal carcinomatosis are eligible. * Adequate organ function.
Exclusion criteria
* Major surgery within four weeks of the start of treatment. * Previous other cancer requiring treatment within the previous two years. * Clinically significant cardiovascular disease. * Any of the following cardiac criteria: * Mean resting corrected QT interval (QTc) \> 470 msec obtained from three ECGs and any factors that increase the risk of QTc prolongation or arrhythmic events * Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG * Known clinically significant active infections not controlled with systemic treatment (bacterial, fungal, viral including HIV positivity). * Gastrointestinal disease or other malabsorption syndromes that would impact drug absorption. * Subjects being treated with or anticipating the need for treatment with strong CYP3A inhibitors or inducers.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities | From initial dose to end of first cycle of treatment, approximately 28 days | Number of participants with first cycle DLTs to determine Mean Tolderable Dose (MTD) and/or RP2D. A DLT is defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications that meets the criteria defined in each subprotocol. The MTD is defined as the highest dose level of repotrectinib given in combination with other anticancer therapy observed to cause a DLT in fewer than 33% of the treated subjects in the first treatment cycle (i.e., Cycle 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Repotrectinib | At Cycle 1 Day 1 and Cycle 1 Day 22 | Cmax is defined as maximum plasma concentration of the drug. |
| Tmax of Repotrecitinib | At Cycle 1 Day 1 and Cycle 1 Day 22 | Tmax is defined is the time to maximum plasma concentration |
| AUC 0-24 of Repotrecitinib | At Cycle 1 Day 1 and Cycle 1 Day 22 | Area under the plasma concentration time-curve. AUC from time 0 to 24 hours after dose. |
| Overall Response Rate (ORR) Assessed the Investigator Using RECIST v1.1. | From screening to end of treatment approximately 10 months | The ORR will be defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat imaging performed at least 4 weeks after initial documentation of response. Participants with a confirmed objective response (CR or PR) will be referred to as responders. Radiographic confirmation of objective tumor response (CR or PR) or disease progression will be based on RECIST v1.1. The ORR will be reported as the percentage of responders by RECIST v1.1 along with the corresponding two-sided 95% Clopper-Pearson exact CI. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = \>=30% decrease in the sum diameters of target lesions. |
| Tmax of Trametinib | At Cycle 1 Day 1 and Cycle 1 Day 22 | Tmax is defined is the time to maximum plasma concentration |
| AUC 0-24 of Trametinib | At Cycle 1 Day 1 and Cycle 1 Day 22 | Area under the plasma concentration time-curve. AUC from time 0 to 24 hours after dose. |
| Cmax of Trametinib | At Cycle 1 Day 1 and Cycle 1 Day 22 | Cmax is defined as maximum plasma concentration of the drug. |
Countries
United States
Participant flow
Pre-assignment details
9 participants enrolled and treated in phase 1. No participants enrolled in phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 Repotrectinib 120 mg QD, Trametinib 2 mg QD | 2 |
| Dose Level 2 Repotrectinib 120 mg QD, Trametinib 1.0 mg QD | 5 |
| Dose Level -2a Repotrectinib 160 mg QD, Trametinib 1.0 mg QD | 2 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 1 | 2 | 0 |
| Overall Study | Other Reasons | 1 | 3 | 2 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level -2a | Total |
|---|---|---|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 21.92 | 61.8 Years STANDARD_DEVIATION 12.74 | 60.5 Years STANDARD_DEVIATION 13.44 | 61.0 Years STANDARD_DEVIATION 12.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 5 Participants | 1 Participants | 6 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 1 Participants | 7 Participants |
| Sex: Female, Male Male | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 2 / 5 | 1 / 2 |
| other Total, other adverse events | 2 / 2 | 5 / 5 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 1 / 5 | 2 / 2 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities
Number of participants with first cycle DLTs to determine Mean Tolderable Dose (MTD) and/or RP2D. A DLT is defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications that meets the criteria defined in each subprotocol. The MTD is defined as the highest dose level of repotrectinib given in combination with other anticancer therapy observed to cause a DLT in fewer than 33% of the treated subjects in the first treatment cycle (i.e., Cycle 1).
Time frame: From initial dose to end of first cycle of treatment, approximately 28 days
Population: All treated participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Number of Participants With Dose Limiting Toxicities | 2 Participants |
| Dose Level 2 | Number of Participants With Dose Limiting Toxicities | 0 Participants |
| Dose Level -2a | Number of Participants With Dose Limiting Toxicities | 2 Participants |
Secondary
AUC 0-24 of Repotrecitinib
Area under the plasma concentration time-curve. AUC from time 0 to 24 hours after dose.
Time frame: At Cycle 1 Day 1 and Cycle 1 Day 22
Population: All Treated Participants with evaluable pharmacokinetic measurements.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level 1 | AUC 0-24 of Repotrecitinib | Cycle 1 Day 1 | 6208.74 h*ng/mL | Geometric Coefficient of Variation 82.59 |
| Dose Level 2 | AUC 0-24 of Repotrecitinib | Cycle 1 Day 1 | 6692.13 h*ng/mL | Geometric Coefficient of Variation 57.48 |
| Dose Level 2 | AUC 0-24 of Repotrecitinib | Cycle 1 Day 22 | 5223.89 h*ng/mL | Geometric Coefficient of Variation 31.06 |
| Dose Level -2a | AUC 0-24 of Repotrecitinib | Cycle 1 Day 1 | 8327.26 h*ng/mL | Geometric Coefficient of Variation 25.27 |
Secondary
AUC 0-24 of Trametinib
Area under the plasma concentration time-curve. AUC from time 0 to 24 hours after dose.
Time frame: At Cycle 1 Day 1 and Cycle 1 Day 22
Population: All Treated Participants with evaluable pharmacokinetic measurements.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level 1 | AUC 0-24 of Trametinib | Cycle 1 Day 1 | 88.77 h*ng/mL | Geometric Coefficient of Variation 6.48 |
| Dose Level 2 | AUC 0-24 of Trametinib | Cycle 1 Day 1 | 20.58 h*ng/mL | Geometric Coefficient of Variation 36.19 |
| Dose Level 2 | AUC 0-24 of Trametinib | Cycle 1 Day 22 | 197.45 h*ng/mL | Geometric Coefficient of Variation 45.52 |
| Dose Level -2a | AUC 0-24 of Trametinib | Cycle 1 Day 1 | 19.27 h*ng/mL | Geometric Coefficient of Variation 13.47 |
Secondary
Cmax of Repotrectinib
Cmax is defined as maximum plasma concentration of the drug.
Time frame: At Cycle 1 Day 1 and Cycle 1 Day 22
Population: All Treated Participants with evaluable pharmacokinetic measurements.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level 1 | Cmax of Repotrectinib | Cycle 1 Day 1 | 656.85 ng/mL | Geometric Coefficient of Variation 37.88 |
| Dose Level 2 | Cmax of Repotrectinib | Cycle 1 Day 1 | 570.86 ng/mL | Geometric Coefficient of Variation 66.02 |
| Dose Level 2 | Cmax of Repotrectinib | Cycle 1 Day 22 | 411.83 ng/mL | Geometric Coefficient of Variation 49.37 |
| Dose Level -2a | Cmax of Repotrectinib | Cycle 1 Day 1 | 569.27 ng/mL | Geometric Coefficient of Variation 20.26 |
Secondary
Cmax of Trametinib
Cmax is defined as maximum plasma concentration of the drug.
Time frame: At Cycle 1 Day 1 and Cycle 1 Day 22
Population: All Treated Participants with evaluable pharmacokinetic measurements.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Level 1 | Cmax of Trametinib | Cycle 1 Day 1 | 15.24 ng/mL | Geometric Coefficient of Variation 20.55 |
| Dose Level 2 | Cmax of Trametinib | Cycle 1 Day 1 | 3.30 ng/mL | Geometric Coefficient of Variation 69.58 |
| Dose Level 2 | Cmax of Trametinib | Cycle 1 Day 22 | 10.55 ng/mL | Geometric Coefficient of Variation 56.36 |
| Dose Level -2a | Cmax of Trametinib | Cycle 1 Day 1 | 2.60 ng/mL | Geometric Coefficient of Variation 29.74 |
Secondary
Overall Response Rate (ORR) Assessed the Investigator Using RECIST v1.1.
The ORR will be defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat imaging performed at least 4 weeks after initial documentation of response. Participants with a confirmed objective response (CR or PR) will be referred to as responders. Radiographic confirmation of objective tumor response (CR or PR) or disease progression will be based on RECIST v1.1. The ORR will be reported as the percentage of responders by RECIST v1.1 along with the corresponding two-sided 95% Clopper-Pearson exact CI. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = \>=30% decrease in the sum diameters of target lesions.
Time frame: From screening to end of treatment approximately 10 months
Population: Efficacy Evaluable Set - all participants who (1) received at least one dose of study treatment with repotrectinib; (2) KRAS mutation determined by a qPCR or NGS test performed in a CLIA laboratory or equivalently accredited diagnostic lab; (3) have a baseline tumor assessment with measurable disease and have at least 1 on-study tumor assessment per RECIST v1.1; and (4) have no major protocol violations that could affect efficacy. (Dose Level 1 and -2a did not meet efficacy evaluable criteria)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Level 2 | Overall Response Rate (ORR) Assessed the Investigator Using RECIST v1.1. | 0 Percentage of Participants |
Secondary
Tmax of Repotrecitinib
Tmax is defined is the time to maximum plasma concentration
Time frame: At Cycle 1 Day 1 and Cycle 1 Day 22
Population: All Treated Participants with evaluable pharmacokinetic measurements.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Level 1 | Tmax of Repotrecitinib | Cycle 1 Day 1 | 3.00 hours (h) |
| Dose Level 2 | Tmax of Repotrecitinib | Cycle 1 Day 1 | 2.00 hours (h) |
| Dose Level 2 | Tmax of Repotrecitinib | Cycle 1 Day 22 | 3.00 hours (h) |
| Dose Level -2a | Tmax of Repotrecitinib | Cycle 1 Day 1 | 4.00 hours (h) |
Secondary
Tmax of Trametinib
Tmax is defined is the time to maximum plasma concentration
Time frame: At Cycle 1 Day 1 and Cycle 1 Day 22
Population: All Treated Participants with evaluable pharmacokinetic measurements.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Level 1 | Tmax of Trametinib | Cycle 1 Day 1 | 1.50 hours (h) |
| Dose Level 2 | Tmax of Trametinib | Cycle 1 Day 1 | 2.00 hours (h) |
| Dose Level 2 | Tmax of Trametinib | Cycle 1 Day 22 | 2.50 hours (h) |
| Dose Level -2a | Tmax of Trametinib | Cycle 1 Day 1 | 2.00 hours (h) |