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Gastrointestinal Stromal TumorsPhase 2REGISTRINCT02638766

Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST

A Phase 2 study testing regorafenib in people with Gastrointestinal Stromal Tumors, run by Grupo Espanol de Investigacion en Sarcomas at 17 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Gastrointestinal Stromal Tumors
What is being tested?
regorafenib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
15 participants
Where
17 sitesin 3 countries
Study dates
Nov 2015to 31 Aug 2021
Phase
Phase 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

  • Patients must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow-up.
  • Informed Consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient´s routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
  • Male or female subjects ≥18 years of age
  • Histologically confirmed GIST KIT/PDGFR wild-type, unresectable or metastatic GIST (confirmed by central laboratory). Paraffin-embedded tumor block must be provided by all subjects during screening period.
  • Screening of mutations done in exon 11, 9, 13 and 17 in KIT gene and in 12 and 18 exons of PDGFR gene
  • Subjects must have at least one measurable lesion according to RECIST v1.1 criteria. A lesion in a previously irradiated area is eligible to be considered as measurable disease as long as there is objective evidence of progression of the lesion prior to study enrolment.
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  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  • Adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment:
  • Total Bilirubin ≤ 1.5 x the upper normal limit (UNL). Documented Gilbert Syndrome is allowed if total bilirubin is mildly elevated (≤6mg/dl).
  • Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x UNL (≤5xUNL for subjects with liver involvement of GIST)
  • Lipase ≤1.5 x UNL
  • Serum Creatinine ≤ 1.5 x UNL
  • Glomerular filtration rate (GFR) ≥ 30ml/mn/1.73 m2 according to the Modified Diet in Renal Disease (MDRD) abbreviated formula.
  • International Normalized Ratio (INR) ≤1.5xUNL and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5xUNL. Subjects who are being treated with an anti-coagulant, such as warfarin or heparin, will be allowed to participate provided that no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR and PTT are stable based on a pre-dose measurement as defined by the local standards of care.
  • Platelet count ≥100000mm3, hemoglobin (Hb) ≥ 9.0 g/dl, absolute neutrophil count (ANC) ≥1500/mm3. Blood transfusions to meet the inclusion criteria will not be allowed.
  • Alkaline phosphatase limit ≤ 2.5 x UNL (≤ 5x UNL for subjects with disease involving the liver)
  • Women of childbearing potential and men must agree to use adequate contraception from the moment of signing the Informed Consent Form until at least 3 months after the last study drug administration. The investigator or a designated associate is requested to advise the subject on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care.
  • Women of childbearing potential must have a blood or urine pregnancy test performed a maximum of 7 days before start of study treatment, and a negative result must be documented before start of study treatment.

Who cannot join

  • Prior systemic treatment for GIST BESIDES IMATINIB. Patients that have relapsed after receiving imatinib during adjuvant setting and patients who are on treatment or have been treated with Imatinib as first line of advanced KIT/PDGFRa wild type GIST are eligible.
  • Cancer other than GIST within 5 years prior to randomization EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, and superficial bladder tumors (Ta (Non Invasive tumor), and Tis (Carcinoma In situ)).
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before the start of study medication.
  • Congestive Heart Failure New York Heart Association (NYHA) ≥ class 2.
  • Unstable angina (angina symptoms at rest, new-onset angina, ie, within the lasts 3 months prior to entering study) or myocardial infarction (MI) within the past 6 months before the start of study medication.
  • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted).
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  • Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90mmHg despite optimal medical management).
  • Subjects with pheochromocytoma.
  • Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months from start of study treatment.
  • Venous thrombotic events such as deep vein thrombosis within the 3 months before the start of study treatment.
  • Ongoing infection > grade 2 National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
  • Known history of human immunodeficiency virus (HIV) infection.
  • Subjects with seizure disorder requiring medication
  • Symptomatic metastasis in brain or meningeal tumors.
  • History of organ allograft.
  • Subjects with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ NCI-CTCAE version 4.03 grade 3 or higher within 4 weeks prior to start of study treatment.
  • Non-healing wound, ulcer, or bone fracture.
  • Renal failure requiring hemo- or peritoneal dialysis.
  • Dehydration NCI-CTCAE version 4.03 grade ≥ 1
  • Substance abuse or medical, psychological, or social conditions that may interfere with the subject´s participation in the study or evaluation of the study results.
  • Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
  • Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study
  • Interstitial lung disease with ongoing signs and symptoms at the time of screening.
  • Subjects unable to swallow oral medication
  • Persistent proteinuria of NCI-CTCAE version 4.03 grade 3 or higher (>3.5g/24hrs), measured by urine protein creatinine ratio on a random urine sample)
  • Any malabsorption condition.
  • Left Ventricular Ejection Fraction (LVEF) < 50% or below the LLN for the institution (whichever is higher).
  • Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 4.03 grade 2 dyspnea)
  • NOTE: It is not necessary to demonstrate disease progression or imatinib intolerance to offer the study entrance.

Trial locations and contacts

17 sites in 3 countries.

17 sites in 3 countries

Spain10 sites

  • Hospital de Cruces

    Barakaldo, 48902

  • Hospital Universitario Vall d´hebron

    Barcelona, 08035

  • Hospital de la Santa Creu i Sant Pau

    Barcelona, 08041

  • Hospital Universitario Gregorio Marañon

    Madrid, 28009

  • Hospital Universitario La Paz

    Madrid, 28046

  • Hospital Universitario de Canarias

    San Cristóbal de La Laguna, Santa Cruz De Tenerife, 38320

  • Hospital Universitario Virgen del Rocío

    Seville, 41013

  • Hospital Universitario Virgen de la Macarena

    Seville, 41071

  • Instituto Valenciano de Oncología

    Valencia, 46009

  • Hospital Universitario Miguel Servet

    Zaragoza, 50009

Other trials in Spain

Italy4 sites

  • Fondazione IRCCS Istituto Dei Tumori di Milano

    Milan

  • Fondazione G Pascale Napoli

    Naples, 80131

  • Policlinico Universitario Campus Bio-Medico

    Roma

  • Istituto di Candiolo - IRCSS

    Torino

Other trials in Italy

France3 sites

  • Institute Bergonie

    Bordeaux

  • Centre Leon Berard

    Lyon

  • Gustave Roussy

    Villejuif

Other trials in France

About this study

Official title: Phase II, Single Arm, Non-randomized and Multicenter Clinical Trial of Regorafenib as a Single Agent in the First-line Setting for Patients With Metastatic and/or Unresectable KIT/PDGFR Wild Type GIST

Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting.

Read the detailed description

The SDH complex is involved in mitochondrial Krebs cycle and defects in the succinate dehydrogenase (SDH) complex have identified, as previously mentioned, in KIT/PDGFR WT. This complex, SDH, has 4 subunits (A-D) and SDH-A or SDH-B are involved in oxidization succinate to fumarate. Therefore, loss of function owing to mutational inactivation leads to the cytoplasmic accumulation of succinate which downregulates prolyl hydroxylase. This enzyme has a negative regulator role of hypoxia-inducible factor 1α (HIF1α) since promotes its proteasomal degradation. Increased levels of HIF1α can enter the nucleus and activate the transcription of vascular endothelial growth factor (VEGFR)24. In fact, the VEGFR expression is higher in KIT/PDGFR WT than in KIT mutant GISTs25.

Approximately 50% of KIT/PDGFR WT show high expression of insulin-like growth factor 1 receptor (IGFR1). This expression may correlate also with the loss of SDH due to IGF autocrine loop26. IGFR signals through both MAPK and PI3K-AKT pathways. As previously mentioned, Regorafenib is able to block MAPK signaling pathway at different levels. Interestingly, early interstitial Cajal cell (ICC) progenitors have a phenotype of KITlowCD44+CD34+IGFR+ while committed lineage of progenitors have KIThighCD44+CD34-IGFR-. Unlike mature or more committed lineage of ICCs, the KITlowCD44+CD34+IGFR+ display resistance to Imatinib in spite of kit signaling pathway activation. Thus Regorafenib could gain advantage over Imatinib for treating KIT/PDGFR WT27,28.

On the other hand, other subsets within of KIT/PDGFR WT as B-RAF mutants or NF1-associated GIST could also be sensitive to Regorafenib. In this later subset, protein expression of phospho-MAPK was seen in 92% of cases in a series of 25 patients29.

Theoretically Regorafenib could also act blocking STAT3, which is activated by RET proto-oncogen, through RET inhibition. STAT3 is implicated as downstream pathway signal in GIST30.

Taken together, the previous data suggests Regorafenib could play a relevant role as upfront treatment of metastatic or unresectable locally advanced KIT/PDGFR WT GIST.

Subjects will receive 160mg (4 tablets) of regorafenib once a day every day for 3 weeks of every 4 week cycle (i.e., 3 weeks on, 1 week off). The study drug will be orally administered.

Doses of study drug may be delayed or reduced in case of clinically significant hematologic and other toxicities. Toxicities will be graded using the CTCAE v 4.03. The modifications of regorafenib are detailed in the protocol for general event, Hand Foot Skin Reaction, Hypertension and drug-related liver function test abnormalities.

Being tested
regorafenib
Keywords
metastatic, unresectable, KIT/PDGFR wild type GIST
Medical subject headings
Gastrointestinal Stromal Tumors, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • regorafenibDrug

    Also called Stivarga

    Treatment with regorafenib 160mg once a day, 3 weeks on / 1 week off in cycles of 28 days

Study groups in NCT02638766
Study groupRoleWhat they receive
Unique armOtherRegorafenib 160mg once a day, frequency: 3 weeks on/1 week off in cycles of 28 days
Receives: Drug: regorafenib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Disease Control Rate

    the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).

    Measured: every 8 weeks during 36 months

Secondary outcomes (8)

  1. Progression free survival

    Number of months without progression

    Measured: every 8 weeks during 36 months

  2. Overall survival

    Number of months alive

    Measured: Every 8 weeks during 36 months

  3. Responses determined by CHOI

    Measure tumor size

    Measured: every 8 weeks during 36 months

  4. Correlation with translational research

    Relation between the clinical data obtained and the data obtained from translational research

    Measured: After 36 months of recruitment

  5. Safety (adverse events following CTCAE v4.03)

    Evaluation of adverse events following CTCAE v4.03

    Measured: Every 28 days until 30 days after last dose

  6. Early metabolic response by PET scan

    Evaluation of metabolic response to treatment

    Measured: After 1 month of starting treatment

  7. Quality of life by EORCT QLQ C30 questionnaire

    EORCT QLQ C30 questionnaires

    Measured: Day 1 of each cycle. Pre-treatment administration

  8. Quality of life by EQ-ED-5L questionnaire

    EQ-ED-5L questionnaires

    Measured: Day 1 of each cycle. Pre-treatment administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Dec 2015 (estimated)
  2. Study startNov 2015
  3. Primary completion31 Aug 2021
  4. Study completion31 Aug 2021

Resources

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 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02638766
Sponsor's protocol ID
REGISTRI (GEIS 40)
Acronym
REGISTRI
Status last verified
Mar 2023
First submitted
11 Nov 2015
Last updated
27 Mar 2023
Results posted
No
Data monitoring committee
No
Individual data sharing
No

Publications

  • Martin-Broto J, Valverde C, Hindi N, Vincenzi B, Martinez-Trufero J, Grignani G, Italiano A, Lavernia J, Vallejo A, Tos PD, Le Loarer F, Gonzalez-Campora R, Ramos R, Hernandez-Jover D, Gutierrez A, Serrano C, Monteagudo M, Leton R, Robledo M, Moura DS, Martin-Ruiz M, Lopez-Guerrero JA, Cruz J, Fernandez-Serra A, Blay JY, Fumagalli E, Martinez-Marin V. REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial. Mol Cancer. 2023 Aug 9;22(1):127. doi: 10.1186/s12943-023-01832-9.

    PubMed 37559050

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing regorafenib in people with Gastrointestinal Stromal Tumors, run by Grupo Espanol de Investigacion en Sarcomas at 17 sites in 3 countries.

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 18 inclusion and 29 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 27 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in Spain, Italy, France. 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 phase mean?

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?

Disease Control Rate (time frame: every 8 weeks during 36 months). 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 NCT02638766, 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 27 Mar 2023.

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