Isocitrate Dehydrogenase Gene Mutation
Conditions
Keywords
Cholangiocarcinoma, Skeletal chondrosarcoma, Glioma, IDH Mutation
Brief summary
An open label single-arm clinical trial to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of HMPL-306 in advanced or metastatic solid tumors with IDH mutation.
Detailed description
HMPL-306 is a dual IDH1/2 inhibitor This is a phase 1, open-label, multicenter study to evaluate the safety and tolerability of HMPL-306 administered orally in the treatment of subjects with advanced or metastatic solid tumors with IDH mutation. The study consists of 2 parts: Part 1 (dose escalation) and Part 2 (dose expansion). The dose escalation part will determine the MTD/RP2D. The dose expansion part will administer the MTD/RP2D to mIDH-positive solid tumor malignancies including, but not limited to, cholangiocarcinoma, skeletal chondrosarcoma, low-grade glioma, perioperative low-grade glioma
Interventions
DRUGHMPL-306
Administered orally QD in a 28-day continuous dosing treatment cycle
Sponsors
Hutchmed
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Subjects are eligible for enrollment into this study if they meet any of the following criteria (NOTE: This is not an exhaustive list): * Subjects aged ≥18 years. * ECOG performance status 0 or 1 * Subjects must have a documented IDH mutation per immunohistochemistry (IHC), polymerase chain reaction (PCR), or next generation sequencing (NGS) testing of tumor tissue. * Subjects must have histologically or cytologically documented, advanced or metastatic solid malignancy of any type that has recurred or progressed on available standard treatment and for which no curative therapy exists. Key
Exclusion criteria
Subjects are not eligible for enrollment into this study if they meet any of the following criteria (NOTE: This is not an exhaustive list): * Subjects who received an investigational agent \<14 days prior to their first day of study drug administration * Subjects who are pregnant or breastfeeding * Subjects with an active severe infection, some treated infections and with an expected or with an unexplained fever \>38.3°C during screening visits or on their first day of study drug administration. * Subjects with some current or prior heart conditions * Subjects taking medications that are known to prolong the QT interval may not be eligible * Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation * Some subjects with some current or prior gastrointestinal or liver diseases * Subjects with inadequate organ function as defined by the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Recommended Phase 2 Dose (RP2D) of HMPL-306 | From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 | RP2D determination took the following criteria under consideration: determination of maximum tolerated dose (MTD) achieved during the dose escalation part and assessment of safety, pharmacokinetics (PK) and pharmacodynamics (PD). The modified toxicity probability interval-2 design was used to perform dose escalation and planned to determine MTD/RP2D. |
| Part 1: Number of Patients With Dose-limiting Toxicities (DLTs) | From the first dose of study drug (Day 1) up to Day 28 of Cycle 1 | DLT:occurrence of any of following treatment-emergent adverse events (TEAEs) during DLT assessment window unless clearly unrelated to study drug/judged by investigator as not clinically significant: 1. Non-hematologic:TEAEs Grade \>=4, Grade 3 except those which recovered to Grade \<=1 within 3 days after supportive therapy administered for nausea,vomiting,diarrhea,constipation,fatigue,electrolyte imbalance;Grade 3 hypothyroidism, adrenal gland or pituitary insufficiency, and inflammatory reactions at tumor site \& Grade 3 hypertension downgraded to Grade \<=1 within 1 week with appropriate supportive therapy. 2. Hematologic:Grade \>=3 febrile neutropenia;Grade 4 neutropenia or thrombocytopenia;Grade 3 thrombocytopenia with clinically significant bleeding in addition to that requiring transfusion;Grade 4 anemia requiring a dose delay of \>=14 days. 3. Any life-threatening complication/abnormality not covered in National Cancer Institute Common Terminology Criteria for AEs version(v) 5.0. |
| Parts 1 and 2: Number of Patients With Treatment-Emergent Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | From the first dose of study drug (Day 1) up to 30 days after the last dose of study drug, approximately 43 months for Part 1 | AE:unfavorable,unintended sign,symptom or disease temporally associated with use of study drug or other protocol-imposed drug, whether or not considered drug related. SAE:AE that resulted in death, was life threatening, inpatient hospitalization/prolongation of existing hospitalization, persistent/significant incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/birth defect, important medical event that jeopardized patient and required medical/surgical intervention to prevent above outcome or signs, symptoms or clinical sequelae of suspected overdose of either study drug or a concomitant medication. TEAE:AE with onset on/after start of study drug until 30 days after last dose or prior to start of subsequent anti-tumor therapy, or AE with onset before start of study drug but worsened in severity after study drug administration or beyond 30 days after last dose or after start of subsequent anti-tumor therapy and treatment-related SAEs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Objective Response Rate (ORR) | Tumor assessments performed every 8 weeks (+/-1 week) from Cycle 1 Day 1 for the first 24 weeks and every 12 weeks (+/-2 weeks) thereafter until end of treatment or end of efficacy follow-up period, approximately 47 months for Part 1 | ORR by response evaluation criteria in solid tumors (RECIST) v1.1 was defined as the percentage of patients with confirmed best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. ORR by response assessment in neuro-oncology criteria (RANO) was defined as the percentage of patients with a BOR of CR or PR or minor response (MR) as determined by the investigator using RANO criteria mentioned in protocol for glioma patients. |
| Parts 1 and 2: Disease Control Rate (DCR) | Tumor assessments performed every 8 weeks (+/-1 week) from Cycle 1 Day 1 for the first 24 weeks and every 12 weeks (+/-2 weeks) thereafter until end of treatment or end of efficacy follow-up period, approximately 47 months for Part 1 | DCR by RECIST v1.1 was defined as percentage of patients with BOR of CR, PR, or stable disease (SD) lasting at least 7 weeks as determined by investigator.CR: disappearance of all target lesions.PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum of diameters.SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Pd, taking as reference the smallest sum on study. Pd: at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (nadir), including baseline. In addition to relative increase of 20%, sum must also demonstrate an absolute increase of at least 5 millimeters (mm). The appearance of 1 or more new lesions was also considered progression. DCR by RANO was defined as percentage of patients with BOR of CR, PR, MR, or SD lasting at least 7 weeks as determined by investigator using RANO criteria mentioned in protocol for glioma patients. |
| Parts 1 and 2: Duration of Response (DoR) | Tumor assessments performed every 8 weeks (+/-1 week) from Cycle 1 Day 1 for the first 24 weeks and every 12 weeks (+/-2 weeks) thereafter until end of treatment or end of efficacy follow-up period, approximately 47 months for Part 1 | DoR by RECIST v1.1 was defined as the time from the first occurrence of confirmed PR or confirmed CR until Pd or death, whichever came first. CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Pd: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. DoR by RANO was defined as the time from the first occurrence of CR or PR or MR using RANO criteria mentioned in protocol for glioma patients, until disease progression or death, whichever comes first. Due to early study termination, Part 2 was never initiated. |
| Parts 1 and 2: Time to Response (TTR) | Tumor assessments performed every 8 weeks (+/-1 week) from Cycle 1 Day 1 for the first 24 weeks and every 12 weeks (+/-2 weeks) thereafter until end of treatment or end of efficacy follow-up period, approximately 47 months for Part 1 | TTR by RECIST v1.1 was defined as the time from start of study treatment until the date of first documented objective response, either confirmed CR or confirmed PR (whichever status was recorded first). CR: disappearance of all target lesions. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. TTR by RANO was defined as the time from start of study treatment until the date of first documented objective response, either CR or PR or MR (whichever status was recorded first) using RANO criteria mentioned in protocol for glioma patients. Due to early study termination, Part 2 was never initiated. |
| Parts 1 and 2: Progression-free Survival (PFS) | Tumor assessments performed every 8 weeks (+/-1 week) from Cycle 1 Day 1 for the first 24 weeks and every 12 weeks (+/-2 weeks) thereafter until end of treatment or end of efficacy follow-up period, approximately 47 months for Part 1 | PFS was defined as the time from the date of first administration of study drug until the first radiographic documentation of objective progression as assessed by investigator using RECIST v1.1 or RANO criteria for glioma patients, or death from any cause. As per RECIST v1.1: Pd: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (nadir), including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression. Criteria for RANO as mentioned in protocol. |
| Parts 1 and 2: Maximum Observed Plasma Concentration (Cmax) of HMPL-306 | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Day 1 of Cycles 1 and 2 for Part 1 | Blood samples were collected at the specified timepoints to determine Cmax of HMPL-306. |
| Parts 1 and 2: Time to Peak Plasma Concentration (Tmax) of HMPL-306 | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Day 1 of Cycles 1 and 2 for Part 1 | Blood samples were collected at the specified timepoints to determine Tmax of HMPL-306. |
| Parts 1 and 2: Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of HMPL-306 | Pre-dose and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours post-dose on Day 1 of Cycles 1 and 2 for Part 1 | Blood samples were collected at the specified timepoints to determine AUC0-24 of HMPL-306. |
| Parts 1 and 2: Maximum Inhibition Rate of Plasma 2-Hydroxyglutaric Acid (2-HG) | From screening (Day -28) until end of treatment, approximately 42 months for Part 1 | Blood samples were collected at the specified timepoints to determine plasma concentrations of 2-HG which was a PD marker. The maximum inhibition rate of 2-HG for patients in different dose groups is presented. |
Countries
Spain, United States
Contacts
STUDY_DIRECTORBo Zhang
Hutchison Medipharma Limited
Participant flow
Recruitment details
This Phase 1, open-label study was conducted in patients with locally advanced or metastatic solid tumors with isocitrate dehydrogenase (IDH) mutations and consisted of dose escalation part (Part 1) and dose expansion part (Part 2).
Pre-assignment details
The study was terminated based on strategic evaluation of the clinical development of HMPL-306 with no safety concerns. At the time of study termination, patients had not entered the dose expansion part (Part 2) of the study (it was never initiated). 42 patients were enrolled in the dose escalation part.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 53.5 years STANDARD_DEVIATION 13.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants |
| Race/Ethnicity, Customized Other | 0 Participants |
| Race/Ethnicity, Customized White | 38 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 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 |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 5 | 1 / 12 | 2 / 6 | 0 / 4 | 0 / 4 | 0 / 5 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 5 | 11 / 12 | 5 / 6 | 4 / 4 | 4 / 4 | 5 / 5 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 2 / 5 | 1 / 12 | 0 / 6 | 2 / 4 | 1 / 4 | 1 / 5 |
Outcome results
None listed