Esophageal NeoplasmsPhase 1/2REPEATNCT02406170
Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma
A Phase 1/2 study testing Regorafenib and Paclitaxel in people with Esophageal Neoplasms and Stomach Neoplasms, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Esophageal Neoplasms, Stomach Neoplasms, Neoplasm Metastasis
- What is being tested?
- Regorafenib and Paclitaxel
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 47 participants
- Where
- 1 siteNetherlands
- Study dates
- Apr 2015to Oct 2019
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 10Show fewer
- 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.
Who cannot join
- 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.
Show all 33Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Academic Medical Center, Medical Oncology
Amsterdam, 1100 DD
About this study
Official title: The REPEAT Trial: Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma, a Phase 1b Study
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.
Read the 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
- Conditions
- Esophageal Neoplasms, Stomach Neoplasms, Neoplasm Metastasis
- Being tested
- Regorafenib, Paclitaxel
- Medical subject headings
- Esophageal Neoplasms, Stomach Neoplasms, Neoplasm Metastasis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RegorafenibDrug
Also called dose escalation scheme
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
PaclitaxelDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Regorafenib+Paclitaxel | Experimental | Regorafenib tolerability will be tested in a dose escalation scheme with a cytotoxic backbone of paclitaxel 80mg/m2. Receives: Drug: Regorafenib; Drug: Paclitaxel |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 4 weeks
Secondary outcomes (5)
Paclitaxel concentration in tumor biopsy
Measured: 2 year
Composite Paclitaxel pharmacokinetics
Area under the plasma concentration versus time curve (AUC), Peak plasma concentration (Cmax)
Measured: 2 year
Expression of regorafenib targets in tumor biopsy samples
Measured: 2 year
Progression free survival
Measured: 2 years
Overall survival
Measured: 2 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Apr 2015 (estimated)
- Study startApr 2015
- Primary completionOct 2019
- Study completionOct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Esophageal NeoplasmsStudies of the same condition, open and under way.
- More trials run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 47 participants (actual)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, H.W.M. van Laarhoven, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Investigators
- Hanneke WM van Laarhoven, MD,PHD, Principal investigator, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02406170
- Sponsor's protocol ID
- NL.51666
- Acronym
- REPEAT
- Status last verified
- Oct 2019
- First submitted
- 26 Mar 2015
- Last updated
- 22 Oct 2019
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 35782751
Study at a glance
From the registry record, last updated by the sponsor on 22 Oct 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The REPEAT Trial: Regorafenib in Combination With Paclitaxel in Advanced Oesophagogastric Carcinoma, a Phase 1b Study
- ClinicalTrials.gov ID
- NCT02406170
- Acronym / sponsor ID
- REPEAT / NL.51666
- Conditions
- Esophageal Neoplasms, Stomach Neoplasms, Neoplasm Metastasis
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 47 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- Apr 2015
- Primary completion
- Oct 2019 (actual)
- Study completion
- Oct 2019 (actual)
- First posted
- 2 Apr 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Regorafenib+Paclitaxel | Experimental | Drug: Regorafenib, Drug: PaclitaxelRegorafenib tolerability will be tested in a dose escalation scheme with a cytotoxic backbone of paclitaxel 80mg/m2. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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
Key exclusion criteria (33 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RegorafenibAlso: dose escalation schemeThe 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 | Drug | Regorafenib+Paclitaxel |
| PaclitaxelPaclitaxel 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. | Drug | Regorafenib+Paclitaxel |
Primary outcome
Toxicity graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0
Time frame: 4 weeks
graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE).
5 secondary outcomes
Paclitaxel concentration in tumor biopsy
Time frame: 2 year
Composite Paclitaxel pharmacokinetics
Time frame: 2 year
Expression of regorafenib targets in tumor biopsy samples
Time frame: 2 year
Progression free survival
Time frame: 2 years
Overall survival
Time frame: 2 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Oct 2019.
- Derived from this study: PubMed 35782751Stroes 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hanneke WM van Laarhoven, MD,PHD principal investigator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Regorafenib and Paclitaxel in people with Esophageal Neoplasms and Stomach Neoplasms, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Oct 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Toxicity graded according to NCI Common Terminology Criteria for Adverse Events Version 4.0 (time frame: 4 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02406170, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Oct 2019.