Clinical Trials /

REGorafenib vsTamoxifen in Patients With Platinum-sensitive OVARian Carcinoma and Isolated Biological Progression

NCT02584465

Description:

The objective of this randomized phase II is to evaluate the benefit of regorafenib for ovarian patients who reported a confirmed elevated CA-125 level under surveillance or bevacizumab, compared with tamoxifen.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Epithelial Tumor
  • Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: REGorafenib vsTamoxifen in Patients With Platinum-sensitive OVARian Carcinoma and Isolated Biological Progression
  • Official Title: A Randomized, Open-label, Comparative, Multicenter, Phase II Study of the Efficacy and Safety of REGorafenib Versus Tamoxifen in Patients With Platinum-sensitive OVARian Carcinoma and Isolated Biological Progression

Clinical Trial IDs

  • ORG STUDY ID: GINECO-OV235
  • NCT ID: NCT02584465

Conditions

  • Ovarian Carcinoma

Interventions

DrugSynonymsArms
TamoxifenA-Tamoxifen
RegorafenibB-Regorafenib

Purpose

The objective of this randomized phase II is to evaluate the benefit of regorafenib for ovarian patients who reported a confirmed elevated CA-125 level under surveillance or bevacizumab, compared with tamoxifen.

Detailed Description

      -  After surgery, most of patients with advanced ovarian/primitive peritoneal /fallopian
           carcinoma received as first line treatment, carboplatin plus paclitaxel plus or minus
           bevacizumab for 6 cycles followed by surveillance or bevacizumab maintenance therapy up
           to one year (GOG (Burger et al.), ICON7 (Perren et al.), French national guidelines
           Saint Paul de Vence (www.arcagy.org)).

        -  This multi-modality approach achieves clinical responses in about 70% of patients,
           although a majority of women eventually relapse and die from disease progression. The
           first sign of relapse can be a progressively rising CA-125 (Tuxen et al.).

        -  Biochemical-recurrent of Epithelial Ovarian Cancer (EOC) is defined as CA-125 elevation
           above normal values without clinical evidence of disease, and can predate clinical
           disease by approximately 3-6 months (Tuxen et al.). Even if CA-125 elevation is a
           harbinger of EOC relapse, the question remains as to whether early therapeutic
           intervention can translate into extending the duration of survival.

        -  A few years ago, Rustin reported from ovarian cancer patients on surveillance after
           first line treatment with isolated elevated CA-125 (without RECIST/symptoms criteria)
           that there was no benefit to initiate a new chemotherapy compared to surveillance
           (Rustin et al. Lancet 2010; Rustin et al. Ann Oncol 2011).

        -  For patients under bevacizumab on maintenance phase at the time of the CA-125 elevation
           without RECIST or symptoms progression, data are scare. In the GOG0218 trial, elevated
           CA-125 did not totally complied with RECIST criteria progression. This study reported
           that the median PFS is longer in patients with continuous bevacizumab (14.1 months),
           compared to patients under placebo (10.3 months), using CA-125 & RECIST criteria,
           supporting the hypothesis that a maintenance treatment with an anti angiogenic agent
           allows delaying disease progression (Burger et al. N. Engl. J. Med. 2011). In an
           analysis of progression-free survival in which data for patients with increased CA-125
           levels were censored, the median progression-free survival was 12.0 months in the
           control group but 18.0 months in the bevacizumab-throughout group (hazard ratio, 0.645;
           P<0.001). The relationship of CA-125 to progressive disease (PD) may be altered in
           bevacizumab (BV)-treated patients. In the Ocean trial elevated CA-125 was associated
           with forthcoming progression for the majority of the patients under bevacizumab (HR
           0.48) in the platinum sensitive population (Aghajanian et al.).

        -  Current international recommendations are to continue the same strategy (surveillance or
           maintenance bevacizumab) until RECIST or symptomatic progression regardless of the
           CA-125 level.

        -  However, some can argue that a waiting attitude is deemed unacceptable due to patient
           anxiety over a rising CA-125 compelling a significant proportion of physicians to
           propose a therapeutic intervention, due to the nearness of the disease progression.

        -  Tamoxifen is an endocrine alternative treatment option in patients with rising CA-125.
           Hurteau et al. studies supported the use of tamoxifen showing a 17% response rate in
           measurable recurrent disease, 13% response rate in platinum resistant disease, observed
           stable disease in 38% of patients lasting a median of 3 months (Hatch, et al).

        -  The use of tamoxifen treatment as a control arm for isolated CA-125 is thus justified
           based on a favorable toxicity profile compared with available cytotoxic agents and the
           lack of interference with subsequent interventions beyond documentation of clinical
           progression (Marckman, et al). As patients have until today no benefit to introduce a
           new chemotherapy regimen for isolated elevated CA-125 (Rustin et al 2010), exploring new
           anti-angiogenic agent could be clinically relevant. Agents that inhibit tumor
           angiogenesis and invasion were considered to be ideal candidates for the experimental
           arm given their potential to prolong the duration of disease-free survival while
           exhibiting a more favorable toxicity profile than cytotoxic drugs.

        -  Pazopanib and other multi-kinase inhibitors such as cediranib, nintenanib reported
           activity in relapsing ovarian cancer (sensitive or resistant population) used alone in
           several phase II trials (Matulonis et al., Ledermann et al., and Friedlander et al.).

        -  Regorafenib is a new oral multi-kinase inhibitor. It inhibits kinases involved in
           angiogenesis (VEGFR 1-3, TIE 2), signaling in the tumor microenvironment (PDGFR-β, FGFR)
           and oncogenesis (KIT, RET and BRAF). Inhibition of tumor growth and formation of
           metastases were shown in vivo. Tumor activity has been reported in a variety of tumor
           types. Regorafenib is approved in Europe for the treatment of metastatic colorectal
           cancer in patients previously treated with, or who are not considered candidates for,
           available therapies. An application for GIST progressing after imatinib and sunitinib
           has obtained the AMM in Europe. The recommended dose is 160 mg taken once daily for 3
           weeks followed by 1 week off therapy.

      The objective of this randomized phase II is to evaluate the benefit of regorafenib for
      ovarian patients who reported a confirmed elevated CA-125 level under surveillance or
      bevacizumab, compared with tamoxifen.
    

Trial Arms

NameTypeDescriptionInterventions
A-TamoxifenActive ComparatorTamoxifen 40mg/day 2 film-coated tablet containing 20 mg of Tamoxifen/day until progression
  • Tamoxifen
B-RegorafenibExperimentalRegorafenib 120mg/day 3 film-coated tablet containing 40 mg of Regorafenib/day, 3 weeks/4 until progression
  • Regorafenib

Eligibility Criteria

        Main Inclusion Criteria:

        I2 Histological confirmation of epithelial ovarian, fallopian tube, or primary peritoneal
        cancer, I3 Rising CA-125 (according to the Rustin/GCIG criteria, see appendix 10))
        occurring more than 6 months after the last platinum-based chemotherapy cycle (platinum
        sensitive), I4 No symptom related to ovarian cancer progression, I6 1 or 2 prior lines of
        platinum-based chemotherapy followed either by surveillance or bevacizumab or olaparib
        (outside therapeutic trial) maintenance, I7 Before randomization, patients must be in CR,
        PR or SD (RECIST version 1.1) under surveillance or maintenance with bevacizumab or
        olaparib,

        I8 Adequate bone marrow, liver and renal functions as assessed by the following laboratory
        tests conducted within 7 days before randomization:

          -  Absolute Neutrophil Count ≥ 1.5 G/L, platelets count ≥ 100 G/L, and hemoglobin ≥
             9g/dL,

          -  AST/ALT ≤ 3 x upper limit of normal (ULN) (or ≤ 5.0 x ULN if liver metastasis) and
             total bilirubin ≤ 1.5 x ULN, Alkaline phosphatase ≤ 2.5 x ULN

          -  Serum creatinine ≤ 1.5 x ULN,

          -  Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m² according to the Modification of
             Diet Renal Disease (MDRD) abbreviated formula

          -  Lipase ≤ 1.5 x ULN

          -  Prothrombine time-international normalized ratio (PT-INR) < 1.5 x ULN. Patients who
             are therapeutically anticoagulated with an agent such as warfarin or heparin will be
             allowed to participate provided that no prior evidence of underlying abnormality in
             this parameter exists, I9 Women of childbearing potential and partners must agree to
             use adequate contraceptive method (if no previous bilateral annexectomies) during the
             whole study period and for up to 6 months after the last dose of study treatment; a
             negative pregnancy test must be obtained prior to randomization,

        Main Exclusion Criteria:

        E4 Past or concurrent history of neoplasm other than ovarian cancer, except for in situ
        carcinoma of the cervix uteri, in situ breast cancer and/or basal cell epithelioma. All
        treats and cures cancer more than 3 years before the study entry is allowed E5 Known
        history or symptomatic metastatic brain or meningeal tumors (head CT or MRI at screening to
        confirm the absence of central nervous system (CNS) disease if the patient has symptoms
        suggestive or consistent with progressive CNS disease), E6 Any prior radiotherapy to the
        pelvis or abdomen; surgery (including open biopsy) within 4 weeks before starting study
        drugs (24 hours for minor surgical procedures), or planned major surgery during the study
        treatment period, E7 Any prior treatment with anti angiogenic agent such as pazopanib,
        nintedanib or cediranib.

        E8 Endocrine therapy administered within 3 years prior to randomization,

        E13 History of any of the following :

          -  abdominal fistula,

          -  gastrointestinal perforation,

          -  intra-abdominal abscess,

          -  any malabsorption condition, E14 Clinically significant bleeding NCI-CTCAE version 4.3
             Grade 3 or higher within 30 days before randomization, E15 Congestive heart failure
             New York Heart Association (NYHA) ≥ class 2, E17 Uncontrolled hypertension (systolic
             blood pressure (BP) > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical
             management), E21 Ongoing infection > Grade 2 according to NCI-CTCAE version 4.3.
             Hepatitis B is allowed if no active replication is present. Hepatitis C is allowed if
             no antiviral treatment is required, E23 Interstitial lung disease with ongoing signs
             and symptoms at the time of screening,
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free survival (PFS)
Time Frame:4 months
Safety Issue:
Description:PFS according to the RECIST 1.1 criteria, based on the investigator's assessment.

Secondary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:4 months
Safety Issue:
Description:
Measure:Time to start of first subsequent chemotherapy (TFST)
Time Frame:5 months
Safety Issue:
Description:
Measure:Second progression-Free Survival (PFS2)
Time Frame:6 months
Safety Issue:
Description:PFS2 based on the investigator's assessment.
Measure:Overall Survival (OS)
Time Frame:7 months
Safety Issue:
Description:
Measure:Adverse events
Time Frame:7 months
Safety Issue:
Description:frequency of adverse events according to MedDRA terms

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:ARCAGY/ GINECO GROUP

Last Updated