Neoplasms

Digestive System Diseases

All Conditions

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Rectal Diseases

Micronutrients

All Drugs and Chemicals

Antineoplastic Agents

Herbal and Botanical

Leucovorin

Fluorouracil

Irinotecan

Cola

Comparator dose and mode of administration The FOLFIRI regimen consists of irinotecan at 180 mg/m2 (IV infusion) on Day 1 of each 14-day cycle, leucovorin at 200 mg/m2 (400 mg/m2 if using d,l-racemic mixture of leucovorin) by IV infusion on Day 1 of each cycle, and 5-FU at 400 mg/m2 as an IV bolus injection followed by a total of 2400 mg/m2 by continuous IV infusion over 46 hours over Days 1 and 2 via an ambulatory programmable pump (the use of an ambulatory pump is optional).

FOLFIRI

Test product: dose and mode of administration:

E7820 is administered orally in tablet form once daily, every day of each 14-day treatment cycle. For the Phase Ib portion, the doses will be 40 mg/day, 70 mg/day, and 100 mg/day, and for the Pase II portion, the dose will be the MTD in combination with Irinotecan, as determined during the Phase ib portion of the study.

The irinotecan regimen consists of an irinotecan dose of 180 mg/m2 by IV infusion once every 2 weeks (Day 1 of each 14-day cycle).

E7820

Harish Dave

The purpose of the Phase Ib portion is to find out the highest dose of study drug that can safely be given when tested in a small group of subjects.

The purpose of the Phase II portion is to find out how safe the study drug is when taken at the highest dose in a larger group of subjects.

This open-label, multicenter, randomized study will consist of a Phase Ib portion: a safety run-in period with 3 ascending doses of E7820; and a Phase II portion: a randomized 2-arm design. Approximately 95 patients with measurable, nonresectable locally advanced or metastatic colorectal adenocarcinoma, who have failed first-line chemotherapy, will be enrolled in the study (approximately 12 to 15 patients in the Phase Ib portion and 80 patients in the Phase II portion). Patients will only participate in either the Phase Ib or the Phase II portion of the study. Patients will receive up to a planned total of 12 cycles of study treatment unless there is occurrence of progressive disease, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurs first. After 12 cycles, patients who demonstrate clinical benefit may continue single agent E7820 for long as clinical benefit is sustained and the treatment is well tolerated. If the treating physician does not feel comfortable discontinuing chemotherapy after 12 cycles, further chemotherapy may be considered following discussion with the medical monitor and sponsor.

Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer

An Open-Label, Multicenter, Randomized Phase Ib/II Study of Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer

MTD: maximum dose that was determined to be safe and tolerable for Phase 2.If two dose limiting toxicities (DLTs) occurred at any dose level,MTD: preceding dose/intermediate dose.DLT was graded according to CTCAE v4.0. Includes \>= Grade 3(G3) peripheral neuropathy,\>=G3 nausea/vomiting despite optimal anti-emetic treatment, any other non-hematologic toxicity of \>=G3(except alopecia, single abnormal laboratory values Investigator judged unlikely related to study therapy, had no clinical correlate, resolved in 7 days, hypersensitivity reaction to any of compounds),Grade 4 neutropenia lasting over 7 days,febrile neutropenia(defined as fever \>=38.5 degrees Celsius with absolute neutrophil count below 1.0\*10\^9 per liter, G3 thrombocytopenia with nontraumatic bleeding(without therapeutic systemic anticoagulation)requiring platelet transfusion,Grade 4 thrombocytopenia (with/without nontraumatic bleeding),any study drug-related death,other toxicity dose escalation committee believed to be DLT.

TEAE is defined as an adverse event that had an onset date, or a worsening in severity on or after the first dose of study drug up to the end of the study. Number of participants with TEAEs are reported based on safety assessments of laboratory tests, physical examination, examining bowel movements, regular measurement of vital signs, eastern cooperative oncology group-performance status and electrocardiogram parameter values. SAE is any untoward medical occurrence that at any dose: resulted in death; life threatening required inpatient hospitalization; resulted in persistent, significant disability; is congenital anomaly/birth defect or medically important due to other reasons than above mentioned criteria. Number of participants with TEAEs and SAEs were reported.

PFS is defined as the time from the date of randomization of a participant until the sooner of (1) the date of first documented progression of such participant's disease (PD) based on Investigator assessments according to response evaluation criteria in solid tumor (RECIST) version (v) 1.1. or; (2) the date of such participant's death due to any cause. PD is defined as at least a 20 percent (%) increase or 5 millimeter (mm) increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.

OS is defined as time from the date of randomization of a participant until the date of death of such participant, regardless of the actual cause of the participant's death.

TTP is defined as time from the date of randomization of a participant until the date of first documented progression of such participant's disease. PD is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking in reference the smallest summed longest diameters on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of 1 or more new lesions was also considered progression.

ORR is defined as percentage of participants in the study whose best overall response is either complete response (CR) or partial response (PR) based on RECIST v1.1. CR is defined as complete disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) must have reduction in short axis to less than 10 mm. PR is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline summed longest diameters.

PharmaBio Development Inc.

Eisai Inc.

Participants received E7820 40 mg tablets, orally, once daily of each 14-day treatment cycle in combination with irinotecan 180 milligram per square meter (mg/m\^2) as an intravenous infusion on Day 1 of each 14-day cycle (once every 2 weeks) for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Phase 1b: Cohort 1: E7820 40 mg + Irinotecan

Participants received E7820 70 mg tablets, orally, once daily of each 14-day treatment cycle in combination with irinotecan 180 mg/m\^2 as an intravenous infusion on Day 1 of each 14-day cycle (once every 2 weeks) for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Phase 1b: Cohort 2: E7820 70 mg + Irinotecan

Participants received E7820 100 mg tablets, orally, once daily of each 14-day treatment cycle in combination with irinotecan 180 mg/m\^2 as an intravenous infusion on Day 1 of each 14-day cycle (once every 2 weeks) for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Phase 1b: Cohort 3: E7820 100 mg + Irinotecan

Participants received E7820 70 mg (changed to 50 mg as per protocol amendment 06) as Recommended Phase 2 dose (RP2D) tablets, orally, once daily of each 14-day treatment cycle on Day 1 with Irinotecan 180 mg/m\^2 as an intravenous infusion on Day 1 of each 14-day cycle for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Phase 2: E7820 70 mg + Irinotecan

Participants received the FOLFIRI regimen, which consisted of irinotecan at 180 mg/m\^2 as an intravenous infusion and leucovorin at 200 mg/m\^2 by intravenous infusion on Day 1 of each cycle, and 5-FU at 400 mg/m\^2 as an intravenous bolus injection followed by a total of 2400 mg/m\^2 by continuous IV infusion over 46 hours over Days 1 and 2 via infusion for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Phase 2: Folfiri

Total

Age, Customized

Sex: Female, Male

The safety population included all the participants who received at least one dose of study drug and who had at least one safety assessment following the first dose.

Eisai Medical Information

Participants received E7820 40 mg, 70 mg and 100 mg tablets, orally, once daily of each 14-day treatment cycle in combination with irinotecan 180 mg/m\^2 as an intravenous infusion on Day 1 of each 14-day cycle (once every 2 weeks) for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until PD, unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Phase 1b, All Participants

The safety population included all the participants enrolled in the Phase 1b portion of this study, except for those who (i) dropped out of the study prior to receiving any study drug, or (ii) were without any safety assessment following the first dose of study drug.

Phase 1b: Maximum Tolerated Dose (MTD) of E7820 With Irinotecan as Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0

TEAEs

SAEs

The safety population included all participants enrolled and randomized to treatment in the Phase 2 portion of this study, except for those who (i) dropped out prior to receiving any study drug, or (ii) were without any safety assessment following the first dose of study drug.

Phase 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Modified intent-to-treat (MITT) analysis set included all participants who were randomized and received at least one dose of study medication without major protocol eligibility violations.

Phase 2: Progression Free Survival (PFS)

MITT analysis set included all participants who were randomized and received at least one dose of study medication without major protocol eligibility violations.

Phase 2: Overall Survival (OS)

Phase 2: Time to Progression (TTP)

Phase 2: Percentage of Participants With Overall Response

Participants received E7820 40 milligram (mg) tablets, orally, once daily of each 14-day treatment cycle in combination with irinotecan 180 milligram per square meter (mg/m\^2) as an intravenous infusion on Day 1 of each 14-day cycle (once every 2 weeks) for up to 12 cycles. After 12 cycles, at the discretion of the Investigator and in consultation with the Medical Monitor, participants who were experiencing clinical benefit continued their assigned treatment until disease progression (PD), unacceptable toxicity, withdrawal of consent, withdrawal by the Investigator, lost to follow-up, or death, whichever occurred first.

Overall Study

Colonic Diseases

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).

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

Placebo

William Schelman, MD, PhD

This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib plus best supportive care (BSC) versus placebo plus BSC in participants with refractory metastatic colorectal cancer (mCRC). 691 participants were randomized to one of the following treatment arms in a 2:1 ratio, fruquintinib plus BSC or placebo plus BSC.

This is a global, randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial to compare the efficacy and safety of fruquintinib in combination with BSC versus placebo in combination with BSC in metastatic colorectal cancer participants who have progressed on, or were intolerant to, chemotherapy, anti-VEGF and anti-EGFR biologics, and TAS-102 or regorafenib. Participants with MSI-H/MMR deficient tumors must have also received an immune checkpoint inhibitor if approved and available and if deemed appropriate. Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available and if deemed appropriate.

Metastatic colorectal cancer cannot be cured by surgery. Therefore, treatment principals are primarily aimed at controlling disease progression and prolonging survival. Standard first- and second-line therapy includes cytotoxic drugs such as 5-fluorouracil, oxaliplatin, and irinotecan; anti-VEGF therapy; and, if RAS wild type, anti-EGFR therapy. After the first two lines of chemotherapy, standard third-line treatment is either TAS-102 or regorafenib. There are currently no effective treatments for patients who have progressed on standard, approved therapies, and treatment options include reuse of prior therapies, clinical trials or BSC. Consequently, there is an unmet medical need for additional safe and effective treatment.

A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer

A Global Multicenter Randomized Placebo-Controlled Phase 3 Trial To Compare The Efficacy And Safety Of Fruquintinib Plus Best Supportive Care To Placebo Plus Best Supportive Care In Patients With Refractory Metastatic Colorectal Cancer

OS was defined as the time (months) from date of randomization to death from any cause. OS was calculated as (date of death or last known alive - date of randomization + 1)/30.4375. Participants without report of death at the time of analysis will be censored at the date last known alive.

PFS was defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator using RECIST v1.1, or death from any cause, whichever comes first. More specifically, PFS was determined using all data until the last evaluable visit prior to or on the date of: (i) radiographic disease progression (PD) per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than the study drugs, whichever was earlier. PD was defined as: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline; an absolute increase of at least 5 mm in the sum of diameters of target lesions; and the appearance of one or more new lesions.

ORR was defined as the percentage of participants who achieved a best overall response of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the investigator. PR: At least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<)10 millimeters (mm).

DCR was defined as percentage of participants achieving a best overall response of confirmed CR, PR, or stable disease (SD) (for at least 7 weeks) per RECIST v1.1, as determined by the investigator. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum on study. 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.

DOR was defined as the time (in months) from the first occurrence of PR or CR by RECIST Version 1.1, until the first date that progressive disease is documented by RECIST Version 1.1, or death, whichever comes first. Only those participants with confirmed responses of CR or PR were included in this analysis. DOR was calculated as (date of death or PD or last assessment - date of first occurrence of confirmed CR or PR + 1)/30.4375.

An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE was considered a TEAE if the onset date was on or after the start of study treatment or if the onset date was missing, or if the AE had an onset date before the start of study treatment but worsened in severity after the study treatment until 37 days after the last dose of study treatment or a new treatment of anti-tumor therapy, whichever was earlier. After this period, treatment-related SAEs were also considered as TEAEs. AEs with an unknown/not reported onset date were also included.

Plasma samples were collected from the participants at the defined time points. Plasma concentrations were measured using a validated, specific, and sensitive liquid chromatography tandem mass spectrometry method. M11 is the active metabolite for the study drug.

QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 milliseconds (msec). QTc: QT interval corrected based on the patient's heart rate. QTcF: An electrocardiographic finding in which the QT interval corrected for heart rate using Fridericia's formula. QTc = QT/∛(RR) RR = Respiration rate.

QT Interval: Ventricular depolarization plus ventricular repolarization Normal Range: 400 to 460 msec. QTc: QT interval corrected based on the patient's heart rate. QTcB: An electrocardiographic finding in which the QT interval corrected for heart rate using Bazzett's formula.

As pre-specified in Exposure-Response final analysis report, fruquintinib exposures response with efficacy and safety endpoints were performed along with data from other clinical studies and the integrated analyses were to be reported separately. Data is not reported for this outcome measure as its analysis is still ongoing and will be reported after study completion.

EORTC QLQ-C30 contains 30 items across 5 functional scales (physical, role, cognitive, emotional, and social), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial difficulties) and global health status/QOL scale. EORTC QLQ-C30 contains 28 questions (4-point scale where 1=Not at all \[best\] to 4=Very Much \[worst\]) and 2 questions (7-point scale where 1=Very poor \[worst\] to 7= Excellent \[best\]). Raw scores are standardized and converted into scale scores ranging from 0 to 100. For global health status/QOL scale, higher scores represent better QOL. A negative change from baseline value indicates patient condition became worst. Change from baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life Scale scores was performed by visit (i.e., cycle), using a restricted maximum likelihood (REML)-based mixed model repeated measures (MMRM) approach.

The EQ-5D-5L is a self-reported health status questionnaire that consisted of six questions used to calculate a health utility score. There were two components to the EQ-5D-5L: a five-item health state profile that assessed mobility, self-care, usual activities, pain/discomfort, and anxiety/depression used to obtain an Index Utility Score and a general VAS score for health status. EQ-5D VAS was used to record participant's rating for his/her current health-related quality of life state on a vertical VAS with scores ranging from 0 to 100, where 0 = worst imaginable health state and 100 = best imaginable health state. The higher the score the better the health status. A negative change from baseline value represents patient condition became worse. Change from baseline in the EQ-5D-5L VAS scores was performed by visit (i.e. cycle), using a REML-based MMRM approach.

EQ-5D-5L consisted of 2 components: health state profile and optional VAS. EQ-5D health state profile had 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problem, 2= slight problem, 3= moderate problem, 4= severe problem, and 5= extreme problem. The response levels collected from the EQ-5D-5L five dimensions as a health profile are converted into an EQ-5D-5L index (utility) scores to represent participants' utility value. The range of health utility index score is from -0.285 to 1, where higher value indicates perfect health and a negative value represents a state worse than dead. Change from baseline in EQ-5D-5L health utility index scores was performed by visit (i.e., cycle), using a REML-based MMRM approach.

Duration of hospital visit was calculated as = stop date - start date + 1. Mean and standard deviation data for duration of hospital visits (in days) by participants was reported in this outcome measure.

Number of participants with any concomitant medications prescribed were reported.

Hutchison Medipharma Limited

All-Cause Mortality data collected during the study was assessed for all randomized participants. Serious AEs and Non-Serious AEs data were collected based on safety population that included all randomized participants who received at least 1 dose of study drug.

Participants received 5 mg of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Fruquintinib + BSC Group

Participants received placebo matched to fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Placebo + BSC Group

Age, Continuous

Ethnicity (NIH/OMB)

Race

Race/Ethnicity, Customized

Intent-to-Treat (ITT) population included all randomized participants.

ITT population included all randomized participants.

Overall Survival (OS)

Progression Free Survival (PFS), as Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST) v1.1

Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Disease Control Rate (DCR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Analysis was performed on subset of participants who had a response. Here, '0' in 'overall number of participants analyzed represents that DOR could only be analyzed in participants who achieved a response. As no participant in the Placebo Plus BSC Group cohort achieved any response, no DOR is available.

Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)

Participants with TEAEs

Participants with Serious TEAEs

SP included all randomized participants who received at least 1 dose of study drug.

Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

Cycle 1 Day 1 - Pre-dose (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 1 - Pre-dose (Plasma Concentrations of M11)

Cycle 1 Day 1 - 1 hour (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 1 - 1 hour (Plasma Concentrations of M11)

Cycle 1 Day 1 - 2 hours (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 1 - 2 hours (Plasma Concentrations of M11)

Cycle 1 Day 1 - 3 hours (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 1 - 3 hours (Plasma Concentrations of M11)

Cycle 1 Day 1 - 4 hours (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 1 - 4 hours (Plasma Concentrations of M11)

Cycle 1 Day 21 - Pre-dose (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 21 - Pre-dose (Plasma Concentrations of M11)

Cycle 1 Day 21 - 1 hour (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 21 - 1 hour (Plasma Concentrations of M11)

Cycle 1 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 21 - 2 hours (Plasma Concentrations of M11)

Cycle 1 Day 21 -3 hours (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 21 - 3 hours (Plasma Concentrations of M11)

Cycle 1 Day 21 - 4 hours (Plasma Concentrations of Fruquintinib)

Cycle 1 Day 21 - 4 hours (Plasma Concentrations of M11)

Cycle 2 Day 21 - Predose (Plasma Concentrations of Fruquintinib)

Cycle 2 Day 21 - Predose (Plasma Concentrations of M11)

Cycle 2 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)

Cycle 2 Day 21 - 2 hours (Plasma Concentrations of M11)

Cycle 3 Day 1 - Pre-dose (Plasma Concentrations of Fruquintinib)

Cycle 3 Day 1 - Pre-dose (Plasma Concentrations of M11)

Cycle 3 Day 21 - Pre-dose (Plasma Concentrations of Fruquintinib)

Cycle 3 Day 21 - Pre-dose (Plasma Concentrations of M11)

Cycle 3 Day 21 - 2 hours (Plasma Concentrations of Fruquintinib)

Cycle 3 Day 21 - 2 hours (Plasma Concentrations of M11)

Cycle 5 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)

Cycle 5 Day 1 - Pre-Dose (Plasma Concentrations of M11)

Cycle 7 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib

Cycle 7 Day 1 - Pre-Dose (Plasma Concentrations of M11)

Cycle 9 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)

Cycle 9 Day 1 - Pre-Dose (Plasma Concentrations of M11)

Cycle 11 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)

Cycle 11 Day 1 - Pre-Dose (Plasma Concentrations of M11)

Cycle 13 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)

Cycle 13 Day 1 - Pre-Dose (Plasma Concentrations of M11)

Cycle 15 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)

Cycle 15 Day 1 - Pre-Dose (Plasma Concentrations of M11)

Cycle 17 Day 1 - Pre-Dose (Plasma Concentrations of Fruquintinib)

Cycle 17 Day 1 - Pre-Dose (Plasma Concentrations of M11)

PK population was used for tabulation of fruquintinib and M11 concentrations from PK plasma samples collected from the Fruquintinib + BSC Group. PK samples for the Placebo + BSC Group were not analyzed. Here, "Overall Number of Participants Analyzed" signifies those participants in the Fruquintinib + BSC Group who were evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at the specified timepoints.

Observed Plasma Concentrations of Fruquintinib and Metabolite M11

Cycle 1 Day 1 - Pre-dose

Cycle 1 Day 1 - 1 hour

Cycle 1 Day 1 - 2 hours

Cycle 1 Day 1 - 3 hours

Cycle 1 Day 1 - 4 hours

Cycle 1 Day 21 - Pre-dose

Cycle 1 Day 21 - 1 hour

Cycle 1 Day 21 - 2 hours

Cycle 1 Day 21 - 3 hours

Cycle 1 Day 21 - 4 hours

Cycle 2 Day 21 - 2 hours

Cycle 3 Day 21 - 2 hours

SP included all randomized participants who received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "number analyzed" signifies those participants who were evaluable at the specified time points.

Change From Baseline of Electrocardiogram (ECG) Results - QTcF Intervals Using Fridericia's Formula

SP included all randomized participants who received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable at the specified timepoints.

Change From Baseline of ECG Results -QTcB Intervals Using Bazzett's Formula

Correlation Between Fruquintinib Exposure-response With Efficacy (OS) and Safety (AEs) Endpoints

Cycle 2

Cycle 3

Cycle 4

ITT population included all randomized participants. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable at the specified timepoints.

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life Scale Score

ITT population included all randomized participants. Here, "Overall Number of Participants Analyzed" signifies those participants who were evaluable for this outcome measure and "Number analyzed" signifies those participants who were evaluable at the specified categories.

Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score

Change From Baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L) Health Utility Index Scores

Health Care Resource Utilization: Duration of Hospital Visits by Participants

Health Care Resource Utilization: Number of Participants With Any Concomitant Medications Prescribed

Participants received 5 milligrams (mg) of fruquintinib oral capsule in combination with BSC once daily for 3 weeks of continuous dosing followed by a 1-week break during a treatment cycle (Each cycle length was 28 days).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Irinotecan Plus E7820 Versus FOLFIRI in Second-Line Therapy in Patients With Locally Advanced or Metastatic Colon or Rectal Cancer	NCT01347645	Colon Cancer Rectal Cancer	FOLFIRI E7820	18 Years -	Eisai Inc.
A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer	NCT04322539	Metastatic Colo... Metastatic Colo...	Fruquintinib Placebo	18 Years -	Hutchmed
A Study of Efficacy and Safety of Fruquintinib (HMPL-013) in Participants With Metastatic Colorectal Cancer	NCT04322539	Metastatic Colo... Metastatic Colo...	Fruquintinib Placebo	18 Years -	Hutchmed

Spots Global Cancer Trial Database for metastatic colon