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Study 516-010 is an open-label Phase 1, drug-drug interaction and QTc study evaluating the effect of sitravatinib on probe substrates for CYP450 enzymes and BCRP and P-gp transporters.
Part 1 of this study is designed to evaluate the potential for drug-drug interactions and QTc effects with sitravatinib monotherapy when administered with probe drugs for specific cytochrome P450 (CYP) enzymes (CYP2C9, CYP2D6, and CYP3A4) and P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters
Part 2 allows for patients to continue sitravatinib treatment with the addition of the checkpoint inhibitor Nivolumab.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Phase 1, Part 1: Sitravatinib monotherapy (DDI cohort) | Experimental | To evaluate the potential for drug-drug interactions (DDI) with sitravatinib monotherapy. To determine the effect of sitravatinib on the pharmacokinetics (PK) of midazolam (CYP3A4 probe substrate), warfarin (CYP2C9 probe substrate), dextromethorphan (CYP2D6 probe substrate), rosuvastatin (BCRP probe substrate), and digoxin (P-gp probe substrate). |
|
| Phase 1, Part 1: Sitravatinib monotherapy (QTc cohort) | Experimental | To evaluate the QTc prolongation risk for sitravatinib in patients with advanced/metastatic solid tumors via C-QTc modeling. |
|
| Phase 1, Part 2: Combination Therapy (both DDI and QTc cohorts) | Experimental | To evaluate safety and tolerability of Sitravatinib treatment with the addition of the checkpoint inhibitor nivolumab. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sitravatinib | Drug | Sitravatinib is a small molecule inhibitor of receptor tyrosine kinases |
|
| Measure | Description | Time Frame |
|---|---|---|
| PK parameters of probe drugs; AUC from time zero to the last data point (AUC-last) | (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib | Part 1; 1-20 Days |
| PK parameters of probe drugs; AUC from time zero to infinity (AUC∞) | (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib | Part 1; 1-20 Days |
| PK parameters of probe drugs; C-max | (warfarin, dextromethorphan, midazolam, digoxin, and rosuvastatin) derived from the plasma concentration time profile before and after oral administration of sitravatinib | Part 1; 1-20 Days |
| Adverse Events | Characterization of AEs by incidence, severity, timing, seriousness & relationship to study treatment | Through study completion, an average of 12 months |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma PK parameters of sitravatinib and M10; C-max | C-max | 1-20 Days |
| Plasma PK parameters of sitravatinib and M10; AUC over the dosing interval (AUC) | AUC over the dosing interval (AUC) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Curtis Chin, MD | Mirati Therapeutics Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Goshen Health | Goshen | Indiana | 46526 | United States | ||
| NEXT Oncology |
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Two Part, Phase 1 study enrolling patients with advanced tumor types into two cohorts: drug-drug interaction (DDI) and QTc. All patients receive the same anticancer treatment.
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|
| Warfarin | Drug | CYP2C9 probe substrate |
|
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| Dextromethorphan | Drug | CYP2D6 probe substrate |
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| Midazolam | Drug | CYP3A4 probe substrate |
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| Digoxin | Drug | P-gp probe substrate |
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| Rosuvastatin | Drug | BCRP probe substrate |
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| Nivolumab | Drug | Nivolumab is a programmed death receptor (PD-1) blocking antibody |
|
|
| 1-20 Days |
| Plasma PK parameters of sitravatinib and M10; trough plasma concentration (C-trough) | trough plasma concentration (C-trough) | 1-20 Days |
| Plasma PK parameters of sitravatinib and M10; time to maximum concentration (t-max) | time to maximum concentration (t-max) | 1-20 Days |
| Adverse Events | Safety characterized by type, incidence, severity, timing, seriousness & relationship to study treatment of adverse events, and laboratory abnormalities | 1-20 Days |
| QT/QTc | ECG data | Part 1: Pre-dose to Day 10 (QTc cohort); Part 1: Pre-dose to Day14 (DDI cohort) |
| Austin |
| Texas |
| 78758 |
| United States |
| NEXT Oncology | San Antonio | Texas | 78229 | United States |
| NEXT Oncology | Fairfax | Virginia | 22031 | United States |
| MultiCare Health System | Tacoma | Washington | 98402 | United States |
| ID | Term |
|---|---|
| C000611865 | sitravatinib |
| D014859 | Warfarin |
| D003915 | Dextromethorphan |
| D000111 | Acetylcysteine |
| D008874 | Midazolam |
| D004077 | Digoxin |
| D000068718 | Rosuvastatin Calcium |
| D000077594 | Nivolumab |
| ID | Term |
|---|---|
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D009019 | Morphinans |
| D053610 | Opiate Alkaloids |
| D000470 | Alkaloids |
| D006572 | Heterocyclic Compounds, Bridged-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
| D010616 | Phenanthrenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D011083 | Polycyclic Compounds |
| D003545 | Cysteine |
| D000603 | Amino Acids, Sulfur |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D004071 | Digitalis Glycosides |
| D002298 | Cardenolides |
| D002301 | Cardiac Glycosides |
| D002297 | Cardanolides |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D006027 | Glycosides |
| D002241 | Carbohydrates |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D005464 | Fluorobenzenes |
| D006845 | Hydrocarbons, Fluorinated |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D013450 | Sulfones |
| D011743 | Pyrimidines |
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
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