A Multi-Center, Open-Label Study of Fruquintinib in Solid Tumors and Colorectal, and Breast Cancers

Hutchison Medipharma Limited129 enrolled

Overview

An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors, metastatic colorectal cancer and metastatic breast cancer.

The study was an open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors. The study consisted of two phases: * A dose escalation phase - Two dose cohorts were evaluated including 3 mg orally QD 3 weeks on/1 week off and 5 mg orally QD 3 weeks on/1 week off. A 3+3 design was used for this portion of the study. * A dose expansion phase - Five cohorts were evaluated in Dose Expansion phase. Cohort A evaluated the MTD/RP2D in patients with advanced solid tumors of any type. Cohort B and Cohort C evaluated the MTD/RP2D in metastatic colorectal cancer patients. Cohort D and Cohort E evaluated the MTD/RP2D in metastatic breast cancer patients. Study was conducted at 9 sites in the United States.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

129

Conditions

Advanced Solid Tumors Metastatic Colon Cancer

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * Fully understand the study and voluntarily sign the ICF; * ≥18years of age; * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Dose Escalation Phase: • Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type (except squamous NSCLC) that has progressed on approved systemic therapy, and for whom no effective therapy or standard of care exists. This cohort is closed to enrollment. Dose Expansion Phase: * Cohort A: Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type (except squamous NSCLC), that has progressed on approved systemic therapy, and for whom no effective therapy or standard of care exists. This cohort is closed to enrollment. * Cohort B: Histologically or cytologically documented mCRC in patients that have progressed on, or had intolerable toxicity with at least 1 FDA-approved third-line systemic therapy (trifluridine/tipiracil or regorafenib). Patients must also have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR therapy for patients who had RAS wild-type tumors. This cohort is currently enrolling. * Cohort C: Histologically or cytologically documented adenocarcinoma of the colon or rectum. Patients must have progressed on, or had intolerable toxicity to, at least 2 prior regimens of standard chemotherapy, but must not have received prior TAS-102 or regorafenib. Prior therapy could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of treatment. Patients must have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy * Cohort D only: Histologically- or cytologically-confirmed Her2-negative, hormone receptor positive (ER+ and/or PR+) breast cancer * Cohort E only: Histologically- or cytologically- confirmed triple negative breast cancer Key Exclusion Criteria: Patients will be excluded from the study, if any of the following criteria is met: * Severe anemia, neutropenia, thrombocytopenia * Moderate to severe renal or hepatic impairment * Uncontrolled hypertension * Risk of, or active hemorrhage: history or presence of active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation of fistulas; or any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation within 6 months prior to screening; * History of a thromboembolic event (including deep vein thrombosis \[DVT\], pulmonary embolism, stroke and/or transient ischemic attack) within 6 months prior to screening; * Patients with squamous NSCLC; * Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) \<50%; * Patients who have ever received a VEGFR inhibitor, except for patients with mCRC enrolled in the dose expansion phase; * Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy; * Systemic small molecule targeted therapies (e.g., tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug; * Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug; * Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first dose of study drug; * Known human immunodeficiency virus (HIV) infection; * Known clinically significant history of liver disease, including cirrhosis, current alcohol abuse or active viral hepatitis. For patients with evidence of chronic hepatitis B (HBV), the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV who are currently on treatment, they are eligible if they have an undetectable HCV viral load; * Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava.; * Women who are pregnant or lactating; * Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; patients requiring steroids within 4 weeks prior to start of study treatment will be excluded; * No other malignancy, except for non-melanoma skin cancer, during the 5 years prior to screening; * Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product; * Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment; * Known hypersensitivity to fruquintinib or any of its excipients. * For Cohort C only: patients who have been previously treated with TAS-102 or regorafenib

Locations (9)

Mayo Clinic Arizona

Phoenix, Arizona, United States

California Cancer Care Associates for Research & Excellence, Inc.

San Marcos, California, United States

St. Joseph Heritage Healthcare

Santa Rosa, California, United States

University of Colorado Cancer Center

Aurora, Colorado, United States

Hem-Onc Associates of the Treasure Coast

Port Saint Lucie, Florida, United States

Mayo Clinic Rochester

Rochester, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, United States

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

Outcomes

Primary Outcomes

Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs)

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.

Time frame: Cycle 1 (cycle length equal to [=] 28 days)

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

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).

Time frame: From first dose of study drug up to 37 days after last dose of study drug (i.e., up to 29 months)

Dose Expansion Phase: Progression Free Survival (PFS) Rate

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.

Time frame: From the first dose of study drug to disease progression, or death, whichever occurred first (i.e., up to 29 months)

Secondary Outcomes

Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib

Cmax of fruquintinib was reported.

Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days)

Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib

Tmax of fruquintinib over a dosing intervals were reported.

Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib

Cmin of fruquintinib was reported.

Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)

Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib

Tmin of fruquintinib was reported.

Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib

AUC0-24 of fruquintinib was reported.

Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib

CL/Fss was calculated as Dose/AUC0-t. As planned, CL/Fss was assessed at Cycle 1 Days 14 and 21 after multiple dose administration in Dose Escalation Phase and Cohort A of Dose Expansion Phase; and at Cycle 1 Day 14 for Cohort B, C, D, E of Expansion Phase.

Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib

Accumulation ratio based on Cmax for Cycle 1 Day 14 was calculated as Day 14 Cmax /Day 1 Cmax and for Cycle 1 Day 21 was calculated as Day 21 Cmax /Day 1 Cmax. Accumulation ratio based on Cmax of fruquintinib was reported.

Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14 and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)

Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib

Accumulation ratio for Cycle 1 Day 14 was calculated as AUC0-24 at Day 14 divided by AUC0-24h at Day 1, and for Cycle 1 Day 21 was calculated as AUC0-24 at Day 21 divided by AUC0-24 at Day 1. Accumulation ratio based on AUC0-24 of fruquintinib was reported.

Dose Escalation and Expansion Phase: Objective Response Rate (ORR)

ORR was defined as the percentage of participants with objective complete response (CR) or partial response (PR) response per RECIST version 1.1. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.

Time frame: From the first dose of study drug until first documentation of best overall response (i.e., up to 29 months)

Dose Escalation and Expansion Phase: Disease Control Rate (DCR)

DCR was defined as the percentage of participants with a best overall response (BOR) of confirmed CR, confirmed PR or stable disease (SD) (for 7 weeks) per RECIST version 1.1. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study \[this might include the baseline sum\]).

Time frame: From the first dose of study drug until first documentation of best overall response (i.e., up to 29 months)

Dose Escalation and Expansion Phase: Duration of Response (DoR)

DoR was defined as the time (in months) from the date of the first objective response (CR or PR) until the date of the documented progression or of death, whichever comes first. DoR was only analyzed for participants whose best overall response (BOR) was either CR or PR. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. 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 (this might include the baseline sum). DoR was calculated using the Kaplan-Meier method.

Time frame: From the date of the first objective response (CR or PR) until the date of the documented disease progression or of death, whichever comes first (i.e., up to 29 months)

Dose Escalation and Expansion Phase: Progression Free Survival (PFS)

PFS was defined as the time (in months) from date of first dosing until the date of an objective disease progression as per RECIST version 1.1 or death due to any cause, whichever comes first. PFS was determined using all the assessment data up until the last evaluable visit prior to or on the date of (i) disease progression as defined by RECIST version 1.1 or death; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, whichever is earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this might include the baseline sum). PFS was calculated using the Kaplan-Meier method.

Time frame: From date of first dose until the date of an objective disease progression or death due to any cause, whichever comes first (i.e., up to 29 months)

Dose Escalation and Expansion Phase: Overall Survival (OS)

OS was defined as the time interval (in months) between the first dose date and the date of death (any cause). OS was calculated using the Kaplan-Meier method.

Time frame: From first dose date to the date of death (due to any cause) (i.e., up to 29 months)

Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size

Tumor size was estimated using data on sum of diameters of target lesion. Percentage change in tumor size from baseline was determined for participants with measurable disease at baseline and derived by the percentage change in the sum of the diameters of target lesions (TLs) compared to baseline. Baseline was defined as the last evaluable tumor assessment result obtained prior to the first administration of study medication.

Time frame: Baseline up to 29 months

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

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 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).