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

NCT03251378 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 2015-013-00US1
• Study Type: interventional
• Target: 129
• Locations: 1 country
• Sites: 9

Brief Summary

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.

Conditions

Advanced Solid Tumors; Metastatic Colon Cancer; Metastatic Breast Cancer; Triple Negative Breast Cancer; HER2-negative Breast Cancer; Hormone Receptor Positive Breast Carcinoma; Rectal Cancer

Keywords

VEGF; colorectal; breast

Outcome Measures

Primary Outcomes (3)

• 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.

  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).

  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.

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

Secondary Outcomes (15)

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

  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

  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: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib

  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

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

  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)

Study Arms (7)

3 mg Dose Escalation

EXPERIMENTAL

3 mg of Fruquintinib (HMPL-013), capsule taken orally, daily, 3 weeks on, 1 week off

Drug: Fruquintinib (HMPL-013)

5 mg Dose Escalation

EXPERIMENTAL

5 mg of Fruquintinib (HMPL-013), capsule taken orally, daily, 3 weeks on, 1 week off

Drug: Fruquintinib (HMPL-013)

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.

Drug: Fruquintinib (HMPL-013)

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.

Drug: Fruquintinib (HMPL-013)

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.

Drug: Fruquintinib (HMPL-013)

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.

Drug: Fruquintinib (HMPL-013)

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.

Drug: Fruquintinib (HMPL-013)

Interventions

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.

Also known as: HMPL-013

3 mg Dose Escalation; 5 mg Dose Escalation; Fruquintinib Expansion Cohort A; Metastatic Breast Cancer (HR positive, HER2 negative) Expansion Cohort D; Metastatic Breast Cancer (TNBC) Expansion Cohort E; Metastatic Colorectal Cancer Expansion Cohort B (prior trifluridine/tipiracil or regorafenib); Metastatic Colorectal Cancer Expansion Cohort C (no prior trifluridine/tipiracil or regorafenib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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;

Sponsors & Collaborators

• Hutchison Medipharma Limited: lead

Study Sites (9)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

California Cancer Care Associates for Research & Excellence, Inc.

San Marcos, California, 92069, United States

Location

St. Joseph Heritage Healthcare

Santa Rosa, California, 95403, United States

Location

University of Colorado Cancer Center

Aurora, Colorado, 80045, United States

Location

Hem-Onc Associates of the Treasure Coast

Port Saint Lucie, Florida, 34952, United States

Location

Mayo Clinic Rochester

Rochester, Minnesota, 55902, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Wang-Gillam A, Schelman W, Ukrainskyj S, Chien C, Gonzalez M, Yang Z, Kania M, Yeckes-Rodin H. Phase 1/1b open-label, dose-escalation study of fruquintinib in patients with advanced solid tumors in the United States. Invest New Drugs. 2023 Dec;41(6):851-860. doi: 10.1007/s10637-023-01395-y. Epub 2023 Oct 5.

  PMID: 37796398 DERIVED

MeSH Terms

Conditions

Colonic Neoplasms; Breast Neoplasms; Triple Negative Breast Neoplasms; Rectal Neoplasms

Interventions

HMPL-013

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Rectal Diseases

Results Point of Contact

• Title: William Schelman, MD, PhD
• Organization: HUTCHMED International

albertof@hutch-med.com

973-306-4490

Study Officials

• William Schelman

  HUTCHMED International

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2017
• First Posted: August 16, 2017
• Study Start: December 11, 2017
• Primary Completion: December 13, 2022
• Study Completion: March 30, 2023
• Last Updated: September 25, 2024
• Results First Posted: September 25, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)