Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Hematinics

Vitamins

Oxaliplatin

Bevacizumab

Leucovorin

Fluorouracil

Irinotecan

Levoleucovorin

Folic Acid

Antineoplastic Agents, Immunological

Angiogenesis Inhibitors

Growth Inhibitors

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antidotes

Protective Agents

Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

ABT-165 plus FOLFIRI (irinotecan, leucovorin, fluorouracil).

Bevacizumab plus FOLFIRI (irinotecan, leucovorin, fluorouracil).

Fluorouracil - bolus

Fluorouracil - infusion

ABT-165

AbbVie Inc.

A study to evaluate the efficacy and tolerability of ABT-165 plus FOLFIRI compared to bevacizumab plus FOLFIRI in participants with previously treated metastatic adenocarcinoma of the colon or rectum.

A Study of ABT-165 Plus FOLFIRI vs Bevacizumab Plus FOLFIRI in Subjects With Metastatic Colorectal Cancer Previously Treated With Fluoropyrimidine, Oxaliplatin and Bevacizumab

Phase 2 Study Comparing Efficacy and Safety of ABT-165 Plus FOLFIRI vs Bevacizumab Plus FOLFIRI in Metastatic Colorectal Cancer Previously Treated With Fluoropyrimidine, Oxaliplatin and Bevacizumab

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.

PFS is defined as the time from randomization until the first occurrence of radiographic progression determined by investigator assessment or death from any cause.

ORR is defined as the proportion of participants with a complete response (CR) or partial response (PR) as determined by a investigator assessment based on Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1.

OS is defined as the time from randomization until death from any cause.

AbbVie

ABT-165 plus FOLFIRI (irinotecan, leucovorin, fluorouracil) IV infusion for a 14 day cycle until disease progression or intolerable toxicity

ABT-165 Plus FOLFIRI

Bevacizumab plus FOLFIRI (irinotecan, leucovorin, fluorouracil) IV infusion for a 14 day cycle until disease progression or intolerable toxicity

Bevacizumab Plus FOLFIRI

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Black or African American

Asian

American Indian or Alaska native

Native Hawaiian or other Pacific Islander

Missing

Race/Ethnicity, Customized

Global Medical Services

Intent to Treat (ITT): includes all randomized participants.

Progression Free Survival (PFS)

Objective Response Rate (ORR)

Overall Survival (OS)

Overall Study

Herbal and Botanical

Cola

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

Race

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

ITT population included all randomized participants.

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).

Fruquintinib + Best Supportive Care (BSC) Group

Antibodies

Antibodies, Monoclonal

Decitabine

Immunoglobulins

Mitogens

Panitumumab

Dacogen™ (decitabine) is a FDA approved drug (NDA - 021790) for the treatment of myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia).

Decitabine will be given on this study at 45 mg/m2 IV over 2 hrs

Dacogen™ (decitabine)

Vectibix® (panitumumab) is a FDA approved drug (BLA-125147) indicated as a single agent for the treatment of EGFR-expressing metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy regimens. Approval is based on progression-free survival; no data demonstrate an improvement in disease-related symptoms or increased survival.

DRUG DESCRIPTION Vectibix® (panitumumab) is a recombinant, human IgG2 kappa monoclonal antibody that binds specifically to the human epidermal growth factor receptor (EGFR). Panitumumab has an approximate molecular weight of 147 kDa. Panitumumab is produced in genetically engineered mammalian (Chinese Hamster Ovary) cells.

Panitumumab will be given on this study at 6 mg/kg, IV over 1 hr

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of ABT-165 Plus FOLFIRI vs Bevacizumab Plus FOLFIRI in Subjects With Metastatic Colorectal Cancer Previously Treated With Fluoropyrimidine, Oxaliplatin and Bevacizumab	NCT03368859	Cancer	Leucovorin Fluorouracil - ... Bevacizumab Fluorouracil - ... ABT-165 Irinotecan	18 Years -	AbbVie
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
KRAS Wild-type Metastatic Colorectal Cancer Trial	NCT00879385	Colorectal Canc...	Dacogen™ (decit... Vectibix® (pani...	18 Years -	University of Utah
Evaluating ABX-EGF in Patients With Metastatic ColorectalCarcinoma	NCT00111774	Colorectal Canc... Carcinoma	ABX-EGF	18 Years -	Amgen
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 colorectal