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JOURNAL ONKOLOGIE – STUDIE
FRESCO-2

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

Rekrutierend

NCT-Nummer:
NCT04322539

Studienbeginn:
Juli 2020

Letztes Update:
21.04.2021

Wirkstoff:
Fruquintinib, Placebo

Indikation (Clinical Trials):
Colorectal Neoplasms

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Hutchison Medipharma Limited

Collaborator:
-

Studienleiter

William Schelman, MD, PhD
Study Director
Hutchison MediPharma International

Kontakt

Studienlocations
(3 von 136)

Alle anzeigen

Studien-Informationen

Detailed Description:

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 advanced colorectal cancer patients who have progressed

on, or were intolerant to, chemotherapy, biologics, and TAS-102 or regorafenib. Patients 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.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Provide written informed consent;

- Age ≥18 years;

- Histologically and/or cytologically documented metastatic colorectal adenocarcinoma.

RAS, BRAF, and microsatellite instability microsatellite instability (MSI)/mismatch

repair (MMR) status for each patient must be documented, according to country level

guidelines;

- Subjects must have progressed on or been intolerant to treatment with either

trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to

TAS-102 or regorafenib if they have received at least 1 dose of either agents and were

discontinued from therapy for reasons other than disease progression. Subjects who

have been treated with both TAS-102 and regorafenib are permitted. Subjects must also

have been previously treated with standard approved therapies: fluoropyrimidine-,

oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and,

if RAS wild-type, an anti-EGFR therapy;

- Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors

must have been treated with immune checkpoint inhibitors if approved and available in

the subject's country unless the patient is ineligible for treatment with a checkpoint

inhibitor;

- Subjects who received oxaliplatin in the adjuvant setting and developed metastatic

disease during or within 6 months of completing adjuvant therapy are considered

eligible without receiving oxaliplatin in the metastatic setting. Subjects who

developed metastatic disease more than 6 months after completion of

oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based

therapy in the metastatic setting to be eligible;

- Body weight ≥40kg;

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;

- Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that

were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there

has been documented progression of those lesions;

- Expected survival >12 weeks.

- For female subjects of childbearing potential and male subjects with partners of

childbearing potential, agreement to use a highly effective form(s) of contraception,

that results in a low failure rate (<1% per year) when used consistently and

correctly, starting during the screening period, continuing throughout the entire

study period, and for 90 days after taking the last dose of study drug. Such methods

include: oral hormonal contraception (combined estrogen/ progestogen, or

progestogen-only) associated with inhibition of ovulation, intrauterine device (IUD),

intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized

partner, or true sexual abstinence in line with the preferred and usual lifestyle of

the subject. Highly effective contraception should always be combined with an

additional barrier method (eg, diaphragm, with spermicide). The same criteria are

applicable to male subjects involved in this clinical trial if they have a partner of

childbirth potential, and male subjects must always use a condom.

- Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if

approved and available in the subject's home country unless the patient is ineligible

for treatment with a BRAF inhibitor.

Exclusion Criteria:

- Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100×109/L, or hemoglobin

<9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of

increasing the likelihood of eligibility is not allowed;

- Serum total bilirubin >1.5 × the upper limit of normal (ULN). Patients with Gilbert

syndrome, bilirubin <2 X ULN, and normal AST/ALT are eligible;

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 × ULN in

patients without hepatic metastases; ALT or AST >5 × ULN in patients with hepatic

metastases;

- Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance

can either be measured in a 24-hour urine collection or estimated by the

Cockroft-Gault equation.

- Urine dipstick protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with greater

than 2+ proteinuria by dipstick must undergo a 24-hour urine collection to assess

urine protein level;

- Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mm Hg and/or

diastolic blood pressure ≥90 mm Hg despite optimal medical management;

- International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin

time (aPTT) >1.5 × ULN, unless the patient is currently receiving or intended to

receive anticoagulants for prophylactic purposes;

- History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage

of an unresected gastrointestinal tumor, history of perforation or fistulas; or any

other condition that could, in the investigator's judgment, result in gastrointestinal

hemorrhage or perforation; within the 6 months prior to screening;

- History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis)

within 2 months prior to screening;

- History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary

embolism (PE), or arterial embolism within 6 months prior to screening.

- Stroke and/or transient ischemic attack within 12 months prior to screening;

- 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% by echocardiogram;

- Mean corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors

that increase the risk of QTc prolongation or risk of arrhythmic events such as

hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or

unexplained sudden death under 40 years of age in a first-degree relative.

- Concomitant medications with a known risk of causing QT prolongation and/or Torsades

de Pointes.

- Systemic anti-neoplastic therapies (except for those described in Exclusion 18) 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 (eg, 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 (i.e., implantation of radioactive seeds) within 60 days prior to the

first dose of study drug.

- Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives,

whichever is longer) before the first dose of study drug;

- Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central

venous catheter placement is allowed) within 60 days prior to the first dose of study

drug or unhealed surgical incision;

- Any unresolved toxicities from a previous antitumor treatment greater than CTCAE v5.0

Grade 1 (except for alopecia or neurotoxicity grade≤2);

- Known human immunodeficiency virus (HIV) infection;

- Known history of active viral hepatitis. For patients with evidence of chronic

hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on

suppressive therapy, if indicated. Patients with HCV infection who are currently on

treatment are eligible if they have an undetectable HCV viral load.

- Clinically uncontrolled active infection requiring IV antibiotics;

- 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

are excluded;

- Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder

ca (Tis and T1) that have been adequately treated 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 (e.g., current alcohol or drug abuse) 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 placebo) or any of its inactive ingredients

including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow

6;

- Subjects who have received prior fruquintinib;

- Live vaccine <28days before the first dose of study drug(s). Seasonal vaccines for

influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are

live vaccines and are not allowed.

Studien-Rationale

Primary outcome:

1. Overall Survival (Time Frame - up to 10 years):
To evaluate the overall survival of fruquintinib plus BSC compared to placebo plus BSC in subjects with refractory mCRC.

Studien-Arme

  • Experimental: fruquintinib plus best supportive care
    In this arm, subjects will receive active study drug plus best supportive care
  • Placebo Comparator: placebo plus best supportive care
    In this arm, subjects will receive placebo plus best supportive care

Geprüfte Regime

  • Fruquintinib (HMPL-013):
    Oral VEGFR inhibitor
  • Placebo:
    Placebo capsule

Quelle: ClinicalTrials.gov


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