We are updating the design of this site. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

This study is currently recruiting participants.
Verified February 2017 by Grupo Espanol de Investigacion en Sarcomas
Sponsor:
ClinicalTrials.gov Identifier:
NCT02638766
First Posted: December 23, 2015
Last Update Posted: February 23, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Bayer
Information provided by (Responsible Party):
Grupo Espanol de Investigacion en Sarcomas
  Purpose
Evaluate the treatment with regorafenib in patients with metastatic and/or unresectable KIT/PDGFR wild type GIST in the first line setting.

Condition Intervention Phase
Gastrointestinal Stromal Tumors Drug: regorafenib Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Grupo Espanol de Investigacion en Sarcomas:

Primary Outcome Measures:
  • Disease Control Rate [ Time Frame: every 8 weeks during 36 months ]
    the sum of complete responses (CR) + partial responses (PR) + stable disease (SD).


Secondary Outcome Measures:
  • Progression free survival [ Time Frame: every 8 weeks during 36 months ]
    Number of months without progression

  • Overall survival [ Time Frame: Every 8 weeks during 36 months ]
    Number of months alive

  • Responses determined by CHOI [ Time Frame: every 8 weeks during 36 months ]
    Measure tumor size

  • Correlation with translational research [ Time Frame: After 36 months of recruitment ]
    Relation between the clinical data obtained and the data obtained from translational research

  • Safety (adverse events following CTCAE v4.03) [ Time Frame: Every 28 days until 30 days after last dose ]
    Evaluation of adverse events following CTCAE v4.03

  • Early metabolic response by PET scan [ Time Frame: After 1 month of starting treatment ]
    Evaluation of metabolic response to treatment


Estimated Enrollment: 39
Study Start Date: November 2015
Estimated Study Completion Date: November 2020
Estimated Primary Completion Date: November 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Unique arm
Regorafenib 160mg once a day, frequency: 3 weeks on/1 week off in cycles of 28 days
Drug: regorafenib
Treatment with regorafenib 160mg once a day, 3 weeks on / 1 week off in cycles of 28 days
Other Name: Stivarga

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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.
  2. Male or female subjects ≥18 years of age
  3. 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.
  4. Screening of mutations done in exon 11, 9, 13 and 17 in KIT gene and in 12 and 18 exons of PDGFR gene
  5. 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.
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  7. 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 thromboplastine 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)
  8. 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.
  9. 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.

Exclusion Criteria:

  1. Prior systemic treatment for metastatic GIST. Patients that have received imatinib during adjuvant setting are eligible only if they have relapsed after a minimum of 2 years from treatment with imatinib.
  2. 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)).
  3. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before the start of study medication.
  4. Congestive Heart Failure New York Heart Association (NYHA) ≥ class 2.
  5. 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.
  6. Cardiac arrhythmias requiring anti-arrhytmic therapy (beta blockers or digoxin are permitted).
  7. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90mmHg despite optimal medical management).
  8. Subjects with pheochromocytoma.
  9. Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within 6 months from start of study treatment.
  10. Venous thrombotic events such as deep vein thrombosis within the 3 months before the start of study treatment.
  11. Ongoing infection > grade 2 National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03
  12. Known history of human immunodeficiency virus (HIV) infection.
  13. Subjects with seizure disorder requiring medication
  14. Symptomatic metastasis in brain or meningeal tumors.
  15. History of organ allograft.
  16. 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.
  17. Non-healing wound, ulcer, or bone fracture.
  18. Renal failure requiring hemo- or peritoneal dialysis.
  19. Dehydration NCI-CTCAE version 4.03 grade ≥ 1
  20. 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.
  21. Known hypersensitivity to the study drug, study drug class, or excipients in the formulation.
  22. Any illness or medical conditions that are unstable or could jeopardize the safety of the subject and his/her compliance in the study
  23. Interstitial lung disease with ongoing signs and symptoms at the time of screening.
  24. Subjects unable to swallow oral medication
  25. 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)
  26. Any malabsorption condition.
  27. Left Ventricular Ejection Fraction (LVEF) < 50% or below the LLN for the institution (whichever is higher).
  28. Pleural effusion or ascites that causes respiratory compromise (≥ NCI-CTCAE version 4.03 grade 2 dyspnea)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02638766


Contacts
Contact: Mamen De Juan, RGN 0034912866807 mamen.crc@grupogeis.org
Contact: Melissa Fernandez-Pinto, MSc 0034912866807 melissa.crc@grupogeis.org

Locations
Italy
Policlinico San Orsola Malpighi Not yet recruiting
Bologna, Italy
Principal Investigator: Guido Biasco         
A. O. Careggi Not yet recruiting
Firenze, Italy
Principal Investigator: Silvia Gasperoni         
Fondazione IRCCS Istituto Dei Tumori di Milano Not yet recruiting
Milan, Italy
Principal Investigator: Paolo G. Casalli         
Istituto Clinico Humanitas Milano Not yet recruiting
Milan, Italy
Principal Investigator: Armando Santoro         
Istituto Nazionale Tumori IRCSS "Fondazione G. Pascale" Not yet recruiting
Naples, Italy
Principal Investigator: Gaetano Apice         
A. O. Universitaria Policlinico Paolo Giaccone Not yet recruiting
Palermo, Italy
Principal Investigator: Giuseppe Badalamenti         
Policlinico Universitario Campus Bio-Medico Not yet recruiting
Roma, Italy
Principal Investigator: Bruno Vincenzi         
Istituto di Candiolo - IRCSS Not yet recruiting
Torino, Italy
Principal Investigator: Giovanni Grignani         
Spain
Hospital Universitario de Canarias Recruiting
La Laguna, Santa Cruz de Tenerife, Spain, 38320
Principal Investigator: Claudia Valverde, MD         
Hospital de Cruces Not yet recruiting
Barakaldo, Spain, 48902
Principal Investigator: Natalia Fuente, MD         
Hospital Universitario Vall d´hebron Recruiting
Barcelona, Spain, 08035
Principal Investigator: Claudia Valverde, MD         
Hospital de la Santa Creu i Sant Pau Recruiting
Barcelona, Spain, 08041
Principal Investigator: A. Lopez Pousa, MD         
Hospital Universitario Gregorio Marañon Not yet recruiting
Madrid, Spain, 28009
Principal Investigator: Rosa Alvarez, MD         
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Principal Investigator: Virginia Martinez Marín, MD         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Principal Investigator: Javier Martín-broto, MD         
Hospital Universitario Virgen de la Macarena Recruiting
Sevilla, Spain, 41071
Principal Investigator: David Vicente Baz, MD         
Instituto Valenciano de Oncología Not yet recruiting
Valencia, Spain, 46009
Principal Investigator: Andres Poveda, MD         
Hospital Universitario Miguel Servet Not yet recruiting
Zaragoza, Spain, 50009
Principal Investigator: Javier Martinez Trufero, MD         
Sponsors and Collaborators
Grupo Espanol de Investigacion en Sarcomas
Bayer
Investigators
Study Chair: Javier Martín-Broto, MD GEIS (GRUPO ESPAÑOL DE INVESTIGACION EN SARCOMAS
Study Director: Virginia Martínez-Marín, MD GEIS (GRUPO ESPAÑOL DE INVESTIGACION EN SARCOMAS
  More Information

Responsible Party: Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier: NCT02638766     History of Changes
Other Study ID Numbers: REGISTRI (GEIS 40)
First Submitted: November 11, 2015
First Posted: December 23, 2015
Last Update Posted: February 23, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
metastatic
unresectable
KIT/PDGFR wild type GIST

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases