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Also known as Fruquintinib, Fruquintinib (HMPL-013)
Fruquintinib in Combination with Sintilimab · 18 trials · 21 indications
Progression-free survival (PFS) is defined as the time from randomization to disease progression assessed by IRC or death due to any cause, whichever occurs first.
Overall Survival (OS) is defined as the time from randomization to death due to any cause.
PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause.
every two months after end of treatment (EOT) observation period at 30 days after the last medication
PFS per RECIST 1.1 by BIRC
ORR per RECIST 1.1 by investigator
Occurrence of completed response or partial response after treatment, assessed by RECIST 1.1
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
To compare the Progressive Free Survival (PFS) of Fruquintinib plus best supportive care (BSC) versus placebo plus BSC in patients advanced non-squamous NSCLC patients who failed to standard second-line chemotherapy according to RECIST 1.1
Area under the plasma concentration-time curve from time 0 to time of the last measurable concentration
Area under the plasma concentration-time curve from time 0 to infinity (if data permit)
To determine the maximum observed plasma concentration of Fruquintinib
area under the plasma concentration-time curve from time 0 to time of the last measurable concentration
area under the plasma concentration-time curve from time 0 to infinity (if data permit)
maximum observed plasma concentration
Pharmacokinetics of fruquintinib by assessment of area under the plasma concentration time curve from zero to the last measurable concentration
Pharmacokinetics of fruquintinib by assessment of area under the plasma concentration curve from zero extrapolated to infinity (if data permit)
Pharmacokinetics of fruquintinib by assessment of maximum plasma fruquintinib concentration
Dose escalation phase: To evaluate the safety and tolerability of fruquintinib plus sintilimab for advanced solid tumors in the dose escalation phase, to observe dose-limiting toxicity (DLT), the maximum tolerated dose (MTD) and/or to determine the recommended phase 2 dose (RP2D) and administration strategy of the combination therapy.
Dose expansion phase (except endometrial cancer \[EMC\] cohort): ORR assessed by investigator
Dose expansion phase (EMC cohort): ORR by IRC
Fruquintinib monotherapy arm: ORR by investigator
Dose-limiting toxicity was defined as: Any Grade 4 non-hematologic toxicity; Any Grade 3 non-hematologic toxicity related to study drug except for nausea/vomiting, diarrhea, constipation, hypertension, and electrolyte imbalances downgraded within 3-days with appropriate supportive treatment; Grade 4 neutropenia lasting \>3 days; Grade 3 febrile neutropenia (absolute neutrophil count \[ANC\] \<1.0\*10\^9 per liter \[/L\] with a single temperature of greater than (\>) 38.3 degree centigrade (°C) or a sustained temperature of greater than or equal to (\>=) 38°C for more than 1 hour); Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; Dose interruption for \>14 days due to toxicity.
TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study medication and no later than 37 days after the date of last study treatment. A serious adverse event (SAE) was any AE that had any of the following characteristics: Fatal (that was, the AE actually caused or led to death, except for deaths caused by the progress of disease); Life threatening (that was, AE, in view of the investigator, places participant at immediate risk of death); Required or prolonged inpatient hospitalization (excluding emergency or outpatient treatment); Resulted in persistent or significant disability/incapacity (that was, the AE resulted in substantial disruption of the participant's ability to conduct normal life functions).
PFS was defined as time from date of first dosing until date of an objective disease progression (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 or death due to any cause, whichever comes first. PFS was determined using all data until last evaluable visit prior to or on date of: (i) radiographic PD per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than study drugs, whichever was earlier. PFS rate was defined as probability of being disease progression free at selected timepoints such as 16 weeks and was calculated using Brookmeyer-Crowley method based on PFS events observed up to 29 months. PD:at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference smallest sum on study, including baseline; an absolute increase of at least 5 millimeter (mm) in sum of diameters of target lesions; and appearance of one or more new lesions.
using RECIST v1.1 progressive disease (PD), using RECIST v 1.1
Safety and tolerance will be evaluated by incidence, severity and outcomes of adverse events (AEs) and categorized by severity in accordance with the NCI CTC AE Version 4.0.
The primary endpoint is evaluation of safety during the first 28-day cycle of therapy following the initiation of multiple dosing of HMPL-013. The safety variables to be evaluated in this study are adverse events, physical examinations, vital signs (specifically including blood pressure), clinical laboratory evaluations including serum chemistry, hematology , and urinalysis (with detailed sediment analysis, proteinuria, and 24-hour urine for collection for protein), and electrocardiograms (ECGs) in triplicate.
| Arm | Type | Description |
|---|---|---|
| Experimental group | EXPERIMENTAL | Patients will be treated with a planned dose of fruquintinib and sintilimab every three weeks until an IRC (independent review committee)-confirmed PD(disease progression) or meeting other discontinuation criteria. |
| Control group | ACTIVE_COMPARATOR | Patients will be treated with TPC (chemotherapy of treating physician's choice, paclitaxel or doxorubicin) every three or four weeks until IRC-confirmed PD or meeting other discontinuation criteria. |
| Fruquintinib Plus Best Supportive Care (BSC) Group | EXPERIMENTAL | Participants will be orally administered Fruquintinib 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days). |
| Placebo Plus BSC Group | PLACEBO_COMPARATOR | Participants will be orally administered Placebo 5 mg in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break (with each cycle length of 28 days). |
| fruquintinib+paclitaxel | ACTIVE_COMPARATOR | treatment arm (fruquintinib+paclitaxel) : Fruquintinib once daily, 3 weeks on/1week off combined with Paclitaxel 80mg/㎡ day1, 8, 15 of 4 weeks cycle. |
| placebo+paclitaxel | PLACEBO_COMPARATOR | control arm (placebo+paclitaxel): Fruquintinib placebo once daily, 3 weeks on/1week off combined with Paclitaxel 80mg/㎡ day1, 8, 15 of 4 weeks cycle. |
| Treatment Arm | ACTIVE_COMPARATOR | All subjects will receive study treatment in 4-week cycles: Fruquintinib, QD, 5mg with best supportive care for 3 consecutive weeks, and then one week off. Tumor assessment will be performed every 4 weeks in the first 2 cycles, and every 8 weeks since the 3rd cycle, until disease progression or death. Subsequent anti-neoplastic treatment and survival status will be followed up after disease progression. |
| Control Arm | PLACEBO_COMPARATOR | All subjects will receive study treatment in 4-week cycles: Placebo, QD, 5mg with best supportive care for 3 consecutive weeks, and then one week off. Tumor assessment will be performed every 4 weeks in the first 2 cycles, and every 8 weeks since the 3rd cycle, until disease progression or death. Subsequent anti-neoplastic treatment and survival status will be followed up after disease |
| Investigational arm | EXPERIMENTAL | fruquintinib, 5 mg, QD, PO, 2 weeks on/1 week off, 3 weeks/cycle; sintilimab, 200 mg, IV infusion, Q3W, 3 weeks/cycle. |
| Control arm (comparator) | ACTIVE_COMPARATOR | axitinib, 5 mg, twice daily (BID), PO, 3 weeks/cycle, dose escalation will be at the investigator 's discretion ;Everolimus, 10 mg, QD, PO, 3 weeks/cycle. |
| Fruquintinib monotherapy factorial study | OTHER | fruquintinib, 5 mg, QD, PO, 3 weeks on/ 1 week off, 4 weeks/cycle. |
| Fruquintinib & Gefitinib | EXPERIMENTAL | Drug: Fruquintinib and Gefitinib |
| Treatment Group | EXPERIMENTAL | The subjects will receive oral Fruquintinib at fasting state 5mg+best supportive care, once daily for the first 3 consecutive weeks and dose holiday for 1 week according to their dose regimens until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent |
| Cohort 1 (healthy subjects) | EXPERIMENTAL | 8 healthy subjects with normal hepatic function will receive a single dose of 5 mg (1x5 mg) fruquintinib |
| Cohort 2 (moderate hepatic impairment) | EXPERIMENTAL | 8 subjects with moderate hepatic impairment will receive a single dose of 2 mg (2 x 1 mg) fruquintinib |
| Cohort 3 (mild hepatic impairment) | EXPERIMENTAL | 8 subjects with mild hepatic impairment will receive a single dose of 5 mg (1 x 5 mg) fruquintinib |
| Cohort 2 (severe renal impairment) | EXPERIMENTAL | 8 subjects with severe renal impairment will be administered 2 mg (2 x 1 mg capsules) fruquintinib |
| Cohort 3 (moderate renal impairment) | EXPERIMENTAL | 8 subjects with moderate renal impairment will be administered 5 mg (a x 5 mg capsule) fruquintinib |
| Part A | EXPERIMENTAL | On Day 1, a single oral dose of dabigatran etexilate 150 mg will be given under fasted conditions and serial PK samples will be collected as indicated on the schedule of events. On Day 5, subjects will receive a single oral dose of fruquintinib 5 mg at approximately 1 hour prior to administration of a single oral dose of dabigatran etexilate 150 mg under fasted conditions and serial PK samples will be collected |
| Part B | EXPERIMENTAL | On Day 1, a single oral dose of rosuvastatin 10 mg will be given under fasted conditions and serial PK samples will be collected as indicated on the schedule of events. On Day 5, subjects will receive a single oral dose of rosuvastatin 10 mg with fruquintinib 5 mg under fasted conditions and serial PK samples will be collected |
| Fed/Fasted | EXPERIMENTAL | fruquintinib 5 mg with food on Day 1 and fruquintinib 5 mg without food on Day 15. 40 mg rabeprazole from Day 23 to Day 29. On Day 29, fruquintinib 5 mg one hour after rabeprazole dose. |
| Fasted/Fed | EXPERIMENTAL | fruquintinib 5 mg without food on Day 1 and fruquintinib 5 mg with food on Day 15. 40 mg rabeprazole from Day 23 to Day 29. On Day 29, fruquintinib 5 mg one hour after rabeprazole dose. |
| VEGFR cohort: | EXPERIMENTAL | Fruquintinib |
| 3 mg Dose Escalation | EXPERIMENTAL | 3 mg of Fruquintinib (HMPL-013), capsule taken orally, daily, 3 weeks on, 1 week off |
| 5 mg Dose Escalation | EXPERIMENTAL | 5 mg of Fruquintinib (HMPL-013), capsule taken orally, daily, 3 weeks on, 1 week off |
| Fruquintinib Expansion Cohort A | EXPERIMENTAL | 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with advanced solid tumors of any type. |
| Metastatic Colorectal Cancer Expansion Cohort B (prior trifluridine/tipiracil or regorafenib) | EXPERIMENTAL | 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have progressed on or had intolerable toxicity to TAS-102, regoragenib, or both. |
| Metastatic Colorectal Cancer Expansion Cohort C (no prior trifluridine/tipiracil or regorafenib) | EXPERIMENTAL | 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic colorectal cancer who have not been treated with TAS-102 or regorafenib. |
| Metastatic Breast Cancer (HR positive, HER2 negative) Expansion Cohort D | EXPERIMENTAL | 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic Her2-negative, hormone receptor positive breast cancer. |
| Metastatic Breast Cancer (TNBC) Expansion Cohort E | EXPERIMENTAL | 5 mg fruquintinib (HMPL-013) capsule taken orally, daily, 3 weeks on, 1 week off in patients with metastatic triple negative (Her2-negative, ER-negative, PR-negative) breast cancer. |
| A- 4mg QD | EXPERIMENTAL | arm A- fruquintinib 4mg once daily, p.o.,continuous;given in 28-days cycles until disease progress, intolerable toxicity or patients withdrawal of consent |
| B- 5mg once daily, 3wks on/1wk off | EXPERIMENTAL | arm B-fruquintinb 5mg once daily,p.o.,3 weeks on/1 week off, given in 28-day cycles until disease progress,intolerable toxicity or patients withdrawal of consent |
| Fruquintinib capsule | EXPERIMENTAL | cohort 1: fruquintinb continuous oral dosing (1mg once a day) cohort 2: fruquintinb continuous oral dosing (2mg once a day) cohort 3: fruquintinb continuous oral dosing (4mg once a day) cohort 4: fruquintinb continuous oral dosing (6mg once a day) cohort 5: fruquintinb continuous oral dosing (5mg once a day) cohort 6: fruquintinb oral dosing, 3 weeks on/1 week off (5mg once a day) cohort 7: fruquintinb oral dosing, 3 weeks on/1 week off (6mg once a day) |
| Name | Type | Description |
|---|---|---|
| fruquintinib | DRUG | Fruquintinib will be orally administrated once daily for 2 consecutive weeks followed by a 1-week break. |
| sintilimab | BIOLOGICAL | Sintilimab will be intravenously administrated on Day 1 every three weeks. |
| paclitaxel | DRUG | 175 mg/m\^2 via IV infusion, once a week for 3 weeks followed by a 1-week break. |
| doxorubicin | DRUG | 60mg/m\^2 via IV infusion, on Day 1 every three weeks. |
| Placebo | DRUG | Placebo capsule |
| fruquintinib +paclitaxel | COMBINATION_PRODUCT | treatment arm(fruquintinib +paclitaxel)- subjects will receive Fruquintinib orally, once daily for 3 wks on/ 1 wk off combined with paclitaxel 80mg/㎡ at day 1,8,15 of 4-week cycle. Patients will receive a cycles of 4 weeks of study treatment or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria. |
| fruquintinib placebo + paclitaxel | COMBINATION_PRODUCT | control arm(fruquintinib placebo + paclitaxel)- subjects will receive Fruquintinib placebo orally, once daily for 3 wks on/ 1 wk off combined with paclitaxel 80mg/㎡ at day 1,8,15 of 4-week cycle. Patients will receive a cycles of 4 weeks of study treatment or until the occurrence of progressive disease (PD), death, unacceptable toxicity, withdrawal of consent or other conditions that meet the end of treatment criteria. |
| fruquintinib+sintilimab | DRUG | fruquintinib, 5 mg, QD, PO, 2 weeks on/1 week off, 3 weeks/cycle; sintilimab, 200 mg, IV infusion, Q3W, 3 weeks/cycle. |
| axitinib / everolimus | DRUG | axitinib, 5 mg, twice daily (BID), PO, 3 weeks/cycle, dose escalation will be at the investigator 's discretion based on clinical; everolimus, 10 mg, QD, PO, 3 weeks/cycle. |
| Gefitinib | DRUG | Gefitinib will be administered orally once daily per 28-day cycle or unacceptable toxicity |
| Dabigatran Etexilate | DRUG | Dabigatran Etexilate will be administered as a single oral dose 150mg on the morning of day 1 and morning of day 5 |
| Rosuvastatin | DRUG | Rosuvastatin will be administered as a single oral dose 10mg on the morning of day 1 and the morning of day 5 |
| fruquintinib with food/fruquintinib without food/fruquintinib with rabeprazole | DRUG | fruquintinib 5 mg with food on Day 1 and fruquintinib 5 mg without food on Day 15. 40 mg rabeprazole from Day 23 to Day 28. 40 mg rabeprazole one hour before 5 mg fruquintinib Day 29. |
| fruquintinib without food/fruquintinib with food/fruquintinib with rabeprazole | DRUG | fruquintinib 5 mg without food on Day 1 and fruquintinib 5 mg with food on Day 15. 40 mg rabeprazole from Day 23 to Day 28. 40 mg rabeprazole one hour before 5 mg fruquintinib Day 29. |
| Fruquintinib in Combination with Sintilimab | DRUG | Fruquintinib plus Sintilimab: Cohort A: Fruquintinib 3 mg QD, oral dosing, 3 weeks on/1 weeks off +Sintilimab 200mg Q4W, intravenous dosing. Cohort B: Fruquintinib 4 mg QD, oral dosing, 3 weeks on/1 weeks off +Sintilimab 200mg Q4W, intravenous dosing Cohort C: Fruquintinib 5 mg QD, oral dosing, 2weeks on/1 weeks off + Sintilimab 200mg Q3W, intravenous dosing Cohort E: Fruquintinib 3 mg QD, continuous, oral dosing, + Sintilimab 200mg Q3W, intravenous dosing Fruquintinib monotherapy arm: Fruquintinib 5 mg QD, oral dosing, 3 weeks on/1 weeks off Patients will be treated until disease progression, death, unacceptable toxicity, loss of follow-up, withdrawal of consent or other conditions meet the end of treatment criteria. |
| Fruquintinib (HMPL-013) | DRUG | Fruquintinib is a small molecule tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3, with a novel chemical structure which belongs to the quinazoline class. |
| fruquintinib+paclitaxel | DRUG | 28-day cycle of fruquintinib qd for 3 weeks followed by 1-week break combined with paclitaxel 80 mg/m2 |
Inclusion Criteria: 1. Have fully understood and voluntarily signed the informed consent form 2. Age 18 to 75 years (inclusive) ; Body mass index (BMI) ≥ 18.5kg/m\^2; 3. Histologically or cytologically confirmed advanced or recurrent endometrial cancer with measurable lesions 4. Patients who previo...
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Fruquintinib+sintilimab is an investigational combination of two anticancer agents studied together in advanced solid tumors, including advanced endometrial cancer and advanced renal cell carcinoma. Fruquintinib is an oral small molecule kinase inhibitor, and sintilimab is an anti-PD-1 antibody. The combination is being developed by HUTCHMED (China) Limited under ticker HCM.
Fruquintinib inhibits FLT1, FLT4, and KDR, which are vascular endothelial growth factor receptors, and it is classified as an inhibitor. Blocking these receptors is intended to suppress tumor angiogenesis. Sintilimab, the partner agent in this combination, is a separate immunotherapy that targets the PD-1 pathway.
HUTCHMED (China) Limited, which trades under the ticker HCM, is developing the fruquintinib plus sintilimab combination. The company is the sponsor of the clinical program evaluating the pairing in advanced endometrial cancer and advanced renal cell carcinoma, among other solid tumor settings.
The fruquintinib plus sintilimab combination is in Phase 3 development. The Phase 3 study is enrolling patients with advanced endometrial cancer. Earlier-stage work in the combination includes a completed Phase 2 trial in advanced renal cell carcinoma. Fruquintinib has received FDA Priority Review and Breakthrough Therapy designations.
The Phase 3 trial NCT06584032 is recruiting 412 women with advanced endometrial cancer in China. The completed Phase 2 FRUSICA-2 trial, NCT05522231, enrolled 265 patients with advanced renal cell carcinoma. Two completed Phase 1 studies, NCT05368805 and NCT05216367, examined drug interactions and hepatic impairment.
Yes, HMPL-013 is another designation for fruquintinib, the oral small molecule kinase inhibitor in this combination. Fruquintinib is also studied with other partners, including paclitaxel, and separately with sintilimab. Searches for fruquintinib plus sintilimab refer to the same combination of these two agents developed by HUTCHMED.