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Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma (REPEAT)

Primary Purpose

Esophageal Neoplasms, Stomach Neoplasms, Neoplasm Metastasis

Status

Completed

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Regorafenib

Paclitaxel

About this trial

This is an interventional treatment trial for Esophageal Neoplasms

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patient must understand, be willing to give consent, and sign a written informed consent form prior to undergoing any study-specific procedure
Male or female and ≥ 18 years of age
Metastatic or non-resectable adeno- or squamous-cell carcinoma of the stomach or oesophagus who failed on first line cytotoxic treatment with a fluoropyrimidine and platinum compound
Tumor accessible for repeated biopsies
Measurable or evaluable disease
Life expectancy of at least 12 weeks
Eastern Cooperative Oncology Group performance status of 0 or 1
Have adequate bone marrow, liver function, and renal function as measured by pre-specified laboratory assessments conducted within 7 days prior to the start of study treatment
If female and of childbearing potential, have a NEGATIVE result on a pregnancy test performed a maximum of 7 days before start of study treatment
If female and of childbearing potential or if male, must agree to use adequate contraception based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 6 months after the last dose of study drug.

Exclusion Criteria:

Prior treatment with regorafenib
Contra-indications for repeated biopsies
Dementia or altered mental status that would prohibit the understanding and giving of informed consent
Inadequate caloric- and/or fluid intake.
Pre-existing motor or sensory neurotoxicity greater than WHO grade 1
Have unresolved toxicity higher than National Cancer Institute-Common Terminology for Adverse Events version 4.0 (NCI-CTCAE v 4.0) Grade 1 attributed to any prior therapy/procedure, excluding alopecia.
Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment
If female and of childbearing potential, be engaged in breast feeding
Be unable to swallow oral tablets
Have congestive heart failure classified as New York Heart Association Class 2 or higher
Have had unstable angina or new-onset angina ≤ 3 months prior to screening
Have had a myocardial infarction ≤ 6 months prior to start of study treatment
Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin
Have uncontrolled hypertension despite optimal medical management
Have pheochromocytoma
Have had arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 3 months prior to the initiation of study treatment
Have an ongoing infection ≥ Grade 2 (NCI-CTCAE v 4.0)
Have a known history of human immunodeficiency virus infection
Have either active hepatitis B or C or chronic hepatitis B or C requiring treatment
Have a seizure disorder requiring medication
Have currently suspected brain metastases
Have a history of organ allograft
Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity
Have had a hemorrhage or a bleeding event > Grade 3 ( NCI-CTCAE v 4.0) within 4 weeks prior to the start of study treatment
Have a non-healing wound, ulcer, or bone fracture
Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained
Have any other serious illness or medical condition that could jeopardize the safety of the patient
Have an unstable illness or medical condition that could jeopardize the safety of the patient and/or his/her compliance
Have a substance abuse, medical, psychological, or social condition that may interfere with participation in the study or evaluation of the study results
Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
Have any malabsorption condition
Using and unable to stop medication that are prohibited due to interaction
Unwilling to stop pommelos, citrus fruit and herbal medicine inducing or inhibiting the CYP system

Sites / Locations

Academic Medical Center, Medical Oncology

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Regorafenib+Paclitaxel

Arm Description

Regorafenib tolerability will be tested in a dose escalation scheme with a cytotoxic backbone of paclitaxel 80mg/m2.

Outcomes

Primary Outcome Measures

Toxicity graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0

graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE).

Secondary Outcome Measures

Paclitaxel concentration in tumor biopsy

Composite Paclitaxel pharmacokinetics

Area under the plasma concentration versus time curve (AUC), Peak plasma concentration (Cmax)

Expression of regorafenib targets in tumor biopsy samples

Progression free survival

Overall survival

Full Information

NCT ID

NCT02406170

First Posted

March 26, 2015

Last Updated

October 18, 2019

Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

1. Study Identification

Unique Protocol Identification Number

NCT02406170

Brief Title

Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma

Acronym

REPEAT

Official Title

The REPEAT Trial: Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma, a Phase 1b Study

Study Type

Interventional

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Completed

Study Start Date

April 2015 (undefined)

Primary Completion Date

October 2019 (Actual)

Study Completion Date

October 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Patients with advanced oesophagogastric cancer (OCG) have a very poor prognosis. After progression on first line therapy, second line chemotherapy with paclitaxel and a VEGF-R2 targeting antibody has a proven benefit on survival. However, no data are available on the combination of paclitaxel with kinase inhibitors in advanced OGC. Here the investigators propose a Phase 1b study to assess the tolerability of regorafenib (an oral multi kinase inhibitor) in combination with paclitaxel and to assess the uptake of paclitaxel in OCG metastasis.

Detailed Description

Rationale: Regorafenib is a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases. Regorafenib demonstrated to increase the overall survival of patients with metastatic colorectal cancer and has been approved by the U.S. Food and Drug Administration (FDA), as well as by The European Medicines Agency (EMA). In a recent phase IB study the combination of regorafenib with FOLFOX or FOLFIRI was shown to be a tolerable treatment regimen as first- or second-line treatment of colorectal cancer. Unfortunately, no data are available showing the effect of regorafenib on chemotherapy uptake in metastases. Here the investigators propose a phase IB study in advanced OGC with cytotoxic treatment consisting of paclitaxel together with regorafenib, to assess the tolerability of the combination as second line therapy for metastasized OGC and to assess the effect of regorafenib on paclitaxel uptake in OGC metastases. Primary objectives: To assess the tolerability of regorafenib combined with paclitaxel. Secondary objectives To assess the effect of regorafenib on uptake of paclitaxel in OGC metastases. To assess the effect of regorafenib on regorafenib targets in OGC metastases and blood samples. To assess the effect of regorafenib on paclitaxel pharmacokinetics. To obtain exploratory data on the efficacy of the combination of regorafenib with paclitaxel. Study design: A phase 1b study of tolerability of regorafenib in combination with paclitaxel. Study population: Patients with advanced oesophagogastric cancer, fit for second line treatment systemic treatment. Intervention: The investigators will perform a phase 1b dose finding study (phase I) and then expand the cohort for evaluating the uptake of paclitaxel in OCG metastasis. Paclitaxel will be tested as cytotoxic backbone for combination with regorafenib in advanced OGC. Paclitaxel will be dosed 80 mg/m2 I.V. infusion on Days 1, 8, and 15 of every 28 day cycle as has been reported previously and has been used in the recent RAINBOW study (NCT01170663). Patients will receive regorafenib daily from day 1-21 of a 28-day cycle. The first cycle starting on day 2 after the first administration of chemotherapy for pharmacodynamics/kinetic purposes. From the second cycle onwards, regorafenib will be dosed from day 1-21. Four different dose levels will be assessed. After the maximum tolerated dose (MTD) has been defined, the corresponding patient cohort will be expanded to 33 patients to assess the effect of regorafenib on uptake of paclitaxel in OGC metastases on day 1 and 15 of the first cycle (phase II). Rationale for the starting dose: Paclitaxel will be dosed 80 mg/m2 I.V. infusion on Days 1, 8, and 15 of every 28 day cycle as has been reported previously and has been used in the recent RAINBOW study The first dose of Regorafenib in the escalation scheme is 80mg per os qd. In phase 1 studies the optimum dose for regorafenib monotherapy has been set at 160mg per os q.d. However, considering the potential side effects of paclitaxel in combination with regorafenib the investigators chose a starting dose of 80mg per os qd. Dose level Paclitaxel dose Regorafenib dose Minimum number patients -1 80mg/m3 i.v 40 mg p.o. qd (starting) 80mg/m3 i.v 80 mg p.o. qd 3 80mg/m3 i.v 120 mg p.o. qd 3 80mg/m3 i.v 160 mg p.o. qd 3

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Esophageal Neoplasms, Stomach Neoplasms, Neoplasm Metastasis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

47 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Regorafenib+Paclitaxel

Arm Type

Experimental

Arm Description

Regorafenib tolerability will be tested in a dose escalation scheme with a cytotoxic backbone of paclitaxel 80mg/m2.

Intervention Type

Drug

Intervention Name(s)

Regorafenib

Other Intervention Name(s)

dose escalation scheme

Intervention Description

The dose of regorafenib will be escalated in fixed increments to establish the maximum tolerated dose (MTD) from day 1-21 against a cytotoxic backbone of paclitaxel 80mg/m2 on days 1, 8 and 15 of a 28 day cycle

Intervention Type

Drug

Intervention Name(s)

Paclitaxel

Intervention Description

Paclitaxel will be administered in combination with regorafenib to serve as a cytotoxic backbone, it will be given in a dose of 80mg/m2 on days 1,8 and 15 of a 28 day cycle.

Primary Outcome Measure Information:

Title

Toxicity graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0

Description

graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE).

Time Frame

4 weeks

Secondary Outcome Measure Information:

Title

Paclitaxel concentration in tumor biopsy

Time Frame

2 year

Title

Composite Paclitaxel pharmacokinetics

Description

Area under the plasma concentration versus time curve (AUC), Peak plasma concentration (Cmax)

Time Frame

2 year

Title

Expression of regorafenib targets in tumor biopsy samples

Time Frame

2 year

Title

Progression free survival

Time Frame

2 years

Title

Overall survival

Time Frame

2 year

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patient must understand, be willing to give consent, and sign a written informed consent form prior to undergoing any study-specific procedure Male or female and ≥ 18 years of age Metastatic or non-resectable adeno- or squamous-cell carcinoma of the stomach or oesophagus who failed on first line cytotoxic treatment with a fluoropyrimidine and platinum compound Tumor accessible for repeated biopsies Measurable or evaluable disease Life expectancy of at least 12 weeks Eastern Cooperative Oncology Group performance status of 0 or 1 Have adequate bone marrow, liver function, and renal function as measured by pre-specified laboratory assessments conducted within 7 days prior to the start of study treatment If female and of childbearing potential, have a NEGATIVE result on a pregnancy test performed a maximum of 7 days before start of study treatment If female and of childbearing potential or if male, must agree to use adequate contraception based on the judgment of the investigator or a designated associate from the date on which the ICF is signed until 6 months after the last dose of study drug. Exclusion Criteria: Prior treatment with regorafenib Contra-indications for repeated biopsies Dementia or altered mental status that would prohibit the understanding and giving of informed consent Inadequate caloric- and/or fluid intake. Pre-existing motor or sensory neurotoxicity greater than WHO grade 1 Have unresolved toxicity higher than National Cancer Institute-Common Terminology for Adverse Events version 4.0 (NCI-CTCAE v 4.0) Grade 1 attributed to any prior therapy/procedure, excluding alopecia. Have had a major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment If female and of childbearing potential, be engaged in breast feeding Be unable to swallow oral tablets Have congestive heart failure classified as New York Heart Association Class 2 or higher Have had unstable angina or new-onset angina ≤ 3 months prior to screening Have had a myocardial infarction ≤ 6 months prior to start of study treatment Have cardiac arrhythmias requiring anti-arrhythmic therapy, with the exception of beta blockers or digoxin Have uncontrolled hypertension despite optimal medical management Have pheochromocytoma Have had arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within 3 months prior to the initiation of study treatment Have an ongoing infection ≥ Grade 2 (NCI-CTCAE v 4.0) Have a known history of human immunodeficiency virus infection Have either active hepatitis B or C or chronic hepatitis B or C requiring treatment Have a seizure disorder requiring medication Have currently suspected brain metastases Have a history of organ allograft Have evidence or history of any bleeding diathesis (including mild hemophilia), irrespective of severity Have had a hemorrhage or a bleeding event > Grade 3 ( NCI-CTCAE v 4.0) within 4 weeks prior to the start of study treatment Have a non-healing wound, ulcer, or bone fracture Have interstitial lung disease with ongoing signs and symptoms at the time informed consent is obtained Have any other serious illness or medical condition that could jeopardize the safety of the patient Have an unstable illness or medical condition that could jeopardize the safety of the patient and/or his/her compliance Have a substance abuse, medical, psychological, or social condition that may interfere with participation in the study or evaluation of the study results Have a known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs Have any malabsorption condition Using and unable to stop medication that are prohibited due to interaction Unwilling to stop pommelos, citrus fruit and herbal medicine inducing or inhibiting the CYP system

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hanneke WM van Laarhoven, MD,PHD

Organizational Affiliation

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Official's Role

Principal Investigator

Facility Information:

Facility Name

Academic Medical Center, Medical Oncology

City

Amsterdam

ZIP/Postal Code

1100 DD

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

35782751

Citation

Stroes CI, Schokker S, Khurshed M, van der Woude SO, Mathot RA, Slingerland M, de Vos-Geelen J, Zucchetti M, Matteo C, van Dijk E, Ylstra B, Thijssen V, Derks S, Godefa T, Dijksterhuis W, Breimer GE, van Delden OM, Verhoeven RH, Meijer SL, Bijlsma MF, van Laarhoven HW. A phase Ib/II study of regorafenib and paclitaxel in patients with beyond first-line advanced esophagogastric carcinoma (REPEAT). Ther Adv Med Oncol. 2022 Jun 28;14:17588359221109196. doi: 10.1177/17588359221109196. eCollection 2022.

Results Reference

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Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma

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