Clinical Trials /

Rogaratinib for BCG Refractory High Risk Non-Muscle Invasive Bladder Cancer With FGFR1/2 Overexpression

NCT04040725

Description:

This research study is studying the safety, tolerability, and tumor activity of the study drug known as rogaratinib as a possible treatment for bladder cancer.

Related Conditions:
  • Bladder Carcinoma
  • Transitional Cell Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Rogaratinib for BCG Refractory High Risk Non-Muscle Invasive Bladder Cancer With FGFR1/2 Overexpression
  • Official Title: Phase II Clinical Trial of Rogaratinib for High Risk Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) With FGFR1 or FGFR3 Gene Overexpression: The Bladder Cancer Signal Seeking Trial (BLASST)-3

Clinical Trial IDs

  • ORG STUDY ID: 19-205
  • NCT ID: NCT04040725

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
RogaratinibRogaratinib

Purpose

This research study is studying the safety, tolerability, and tumor activity of the study drug known as rogaratinib as a possible treatment for bladder cancer.

Detailed Description

      This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational drug to learn whether the drug works in treating a
      specific disease. "Investigational" means that the drug is being studied. The U.S. Food and
      Drug Administration (FDA) has not approved rogaratinib as a treatment for any disease.

      In this research study, the investigators are studying rogaratinib in bladder cancer that has
      not responded to BCG and overexpresses a protein called FGFR1 or 3.

        -  Mutations in FGFR help bladder cancer grow. In metastatic cancers that express FGFR 1 or
           3, rogaratinib and other inhibitors of FGFR have shown to be an effective treatment

        -  Rogaratinib is an oral drug that inhibits FGFR

        -  To date, no therapy has been shown to be effective in controlling bladder cancer after
           BCG does not work.
    

Trial Arms

NameTypeDescriptionInterventions
RogaratinibExperimentalRogaratinib is administered orally twice daily Rogaratinib is held for 72 hours before cystoscopy/TURBT and if no complications are seen, treatment is resumed 24 hours after the TURBT
  • Rogaratinib

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female patients ≥ 18 years of age (at least age of legal maturity)

          -  Have a histologically-confirmed diagnosis of high risk non-muscle-invasive (T1, High
             Grade Ta and/or CIS) transitional cell carcinoma of the bladder. Subjects with tumors
             of mixed transitional/non-transitional cell histology are not allowed.

          -  In subjects with Ta and T1, have undergone complete TURBT as characterized by:

               -  Attainment of a visually complete resection

               -  Residual CIS not amenable to complete transurethral resection is acceptable

               -  The most recent cystoscopy / TURBT must have been performed within 8 weeks prior
                  to the first dose of trial treatment

          -  Have been treated with adequate BCG therapy and have developed NMIBC that is
             unresponsive to BCG therapy. Adequate BCG therapy must include: An induction course
             with at least 5 instillations of BCG (adequate induction); and at least 7
             instillations of BCG within 9 months of the first instillation of adequate induction
             therapy. BCG unresponsive high risk NMIBC is defined as: Stage progression at 3 months
             (±4 weeks) despite adequate induction therapy (e.g., Ta to T1, or CIS to T1; note:
             adequate induction therapy only, defined above, is required in this case); or
             Persistent high risk NMIBC at 6 months (±4 weeks) after adequate BCG therapy or
             Recurrent high risk NMIBC within 9 months of the last BCG instillation despite
             adequate BCG therapy.

          -  Have elected not to undergo, or are considered ineligible for radical cystectomy, as
             determined by the treating surgeon. Reasons for ineligibility or refusal of radical
             cystectomy should be discussed with the subject as part of the informed consent
             process and should be captured on the appropriate case report form. Ineligibility
             factors for radical cystectomy may include, but are not limited to:

               -  Cardiovascular disease (e.g. recent acute coronary syndrome, arrhythmia, heart
                  failure)

               -  Chronic obstructive pulmonary disease that would preclude a safe surgical
                  procedure, as determined by the treating surgeon

               -  Poor performance status (e.g. ECOG >2)

               -  Prior major abdominal and pelvic surgery, that would preclude a safe surgical
                  procedure, as determined by the treating surgeon

          -  High FGFR 1/3 mRNA expression levels (RNAscope score of 3+ or 4+; measurement is part
             of the protocol) in archival or fresh tumor biopsy specimen

          -  Existence of archival or fresh tumor biopsy specimen for FGFR1/3 mRNA expression
             testing. Patients who don't have archival tissue specimens meeting eligibility
             requirements may undergo a biopsy. Acceptable samples include core needle biopsies for
             deep tumor tissue (minimum three cores) or excisional, incisional, punch, or forceps
             biopsies for cutaneous, subcutaneous, or mucosal lesions.

          -  Ability to understand and signing of the written patient information/informed consent
             form (PI/ICF) for FGFR testing

          -  Ability to understand and signing of the written PI/ICF for study treatment
             eligibility. Signed informed consent form must be available before any study-specific
             procedure for the respective study parts may begin.(PI/ICF for study treatment
             eligibility must be offered only after positive results in FGFR testing study received
             by site.)

          -  Eastern Cooperative Oncology Group performance status 0 or 1

          -  Adequate bone marrow, liver and renal function as assessed by laboratory requirements
             conducted within 14 days before registration:

               -  Absolute neutrophil count (ANC) ≥ 1,500/mm3 (without granulocyte
                  colony-stimulating factor support within 2 weeks before the first study drug
                  administration)

               -  Hemoglobin ≥ 10 g/dL (without transfusion or erythropoietin within 4 weeks before
                  the first study drug administration)

               -  Platelet count ≥ 100,000/mm3 (without transfusion within 2 weeks before the first
                  study drug administration)

               -  Total bilirubin ≤ 1.5 x the upper limit of normal (ULN). Total bilirubin ≤ 3 x
                  ULN for patients with known Gilbert syndrome.

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN

               -  Alkaline phosphatase ≤ 2.5 times ULN

               -  Lipase and amylase ≤ 2 x ULN

               -  Serum albumin ≥ 2.5 g/dl

               -  Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 according to the
                  modification of diet in renal disease (MDRD) abbreviated formula.

        Note: at the investigator's discretion, an estimated creatinine clearance result <60
        mL/min/1.73m² may be verified by measurement of creatinine clearance based on 24-hour urine
        collection or using EDTA, inulin, GFR scan. INR ≤ 1.5 x ULN and PTT or activated PTT (aPTT)
        ≤ 1.5 x ULN. Patients being treated with anticoagulant, e.g. warfarin or heparin, will be
        allowed to participate provided no prior evidence of an underlying abnormality in these
        parameters exists and they are on a stable dose as defined by the local standard of care.

          -  Negative serum pregnancy test in women of childbearing potential (performed within 7
             days before the first treatment). Negative results must be available before the first
             study drug administration. Females are considered of childbearing potential unless
             they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation,
             or bilateral oophorectomy) or they are naturally postmenopausal for at least 12
             consecutive months.

          -  Women and men of reproductive potential must agree to use adequate contraception when
             sexually active. This applies for the time period between signing of the informed
             consent form and until at least 5 months after the last study drug administration. The
             definition of adequate contraception will be based on the judgment of the investigator
             and on local requirements. Acceptable methods of contraception include, but are not
             limited to, (i) condoms (male or female) with or without a spermicidal agent; (ii)
             diaphragm or cervical cap with spermicide; (iii) intra-uterine device; (iv)
             hormone-based contraception.

          -  Recovery to National Cancer Institute's Common Terminology Criteria for Adverse
             Events, version 5.0 (NCI CTCAE v.5.0) Grade 0 or 1 level or recovery to baseline
             preceding the prior treatment from any previous drug / procedure-related toxicity
             (patients with persistent alopecia of any grade, and/or anemia [hemoglobin ≥ 10 g/dL]
             can be included)

        Exclusion Criteria:

          -  Has muscle invasive (i.e. T2, T3, T4) locally advanced non-resectable or metastatic
             urothelial carcinoma.

          -  Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) non-muscle
             invasive transitional cell carcinoma of the urothelium.

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment.

          -  Has undergone any intervening intravesical chemotherapy or immunotherapy from the time
             of most recent cystoscopy/TURBT to starting trial treatment. (Note: intravesical
             treatment given as part of the most recent cystoscopy / TURBT is allowed.)

          -  Previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase
             inhibitors including rogaratinib or FGFR-specific antibodies).

          -  Previous or concurrent cancer except: cervical carcinoma in situ, treated basal-cell
             carcinoma or squamous cell skin cancer, localized prostate cancer treated with
             curative intent and known absence of prostate-specific antigen (PSA) relapse or
             incidental prostate cancer (T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL undergoing
             active surveillance and treatment-naïve), or any other cancer curatively treated > 3
             years before the first study drug administration.

          -  History or current condition of an uncontrolled cardiovascular disease including any
             of the following conditions:

               -  Congestive heart failure (CHF) NYHA Class 2 or greater, unstable angina (symptoms
                  of angina at rest)

               -  New-onset angina (within last 3 months before the first study drug
                  administration)

               -  Myocardial infarction (MI) within past 6 months before the first study drug
                  administration

               -  Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with
                  arrhythmia not requiring therapy or under control with anti-arrhythmic therapy
                  such as beta-blockers or digoxin are eligible.

          -  Patients with known coronary artery disease, or congestive heart failure not meeting
             the above criteria, must be on a stable medical regimen that is optimized in the
             opinion of the treating physician, in consultation with a cardiologist if appropriate.

          -  Known human immunodeficiency virus (HIV) infection.

          -  Active hepatitis B virus (HBV; chronic or acute; defined as having a known positive
             hepatitis B surface antigen [HBsAg] test at the time of screening) or hepatitis C
             infection requiring treatment. Patients with past HBV infection or resolved HBV
             infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of
             HBsAg) are eligible if HBV DNA is negative. Patients positive for hepatitis C virus
             (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

          -  Active tuberculosis.

          -  Treatment with therapeutic oral or I.V. antibiotics within 2 weeks before the first
             study drug administration. Patients receiving prophylactic antibiotics (e.g. for
             prevention of a urinary tract infection or to prevent chronic obstructive pulmonary
             disease exacerbation) are eligible.

          -  Any hemorrhage / bleeding event CTCAE v.5.0 ≥ Grade 3 within 4 weeks before the first
             study drug administration.

          -  Serious, non-healing wound, ulcer, or bone fracture.

          -  Known hypersensitivity to any of the study drugs, study drug classes, or excipients in
             the formulation.

          -  Any malabsorption condition.

          -  Current diagnosis of any retinal disorders including retinal detachment, retinal
             pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion. An
             ophthalmological exam with optical coherence tomography is required within 30 days of
             the date of registration.

          -  Peripheral sensory neuropathy of CTCAE v.5.0 Grade 2 or higher.

          -  Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g.
             parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis,
             paraneoplastic hypercalcemia).

          -  Concomitant therapies that are known to increase serum phosphate levels (i.e.
             antacids, laxatives oral/rectal, oral phosphate binders, potassium phosphate) and that
             cannot be discontinued or switched to a different medication before the first study
             drug administration.

          -  Any condition that is unstable or could jeopardize the safety of the patient and their
             compliance in the study.

          -  Clinically active infections (CTCAE v. 5.0 ≥ Grade 1) within 2 weeks before the first
             study drug administration.

          -  Seizure disorder requiring medication.

          -  History of organ allograft.

          -  Evidence or history of bleeding diathesis or coagulopathy.

          -  Women who are actively breastfeeding.

          -  Use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 are not permitted for
             2 weeks before the first study drug administration or during the study.

          -  Autologous bone marrow transplant or stem cell rescue within 4 months before the first
             study drug administration.

          -  Major surgery, open biopsy, or significant traumatic injury within 4 weeks before the
             first study drug administration (central line surgery is not considered major
             surgery).

          -  Renal failure requiring peritoneal dialysis or hemodialysis.

          -  Systolic/diastolic blood pressure ≤ 100/60 mmHg and concurrent heart rate ≥ 100/min.

          -  Inability to swallow oral tablets.

          -  Close affiliation with the investigational site; e.g. a close relative of the
             investigator or a dependent person (e.g. employee of or student at the investigational
             site).

          -  Substance abuse, medical, psychological or social conditions that may interfere with
             the patient's participation in the study or evaluation of the study results.

          -  Arterial or venous thrombotic events or embolic events such as cerebrovascular
             accident (including transient ischemic attacks), deep vein thrombosis or pulmonary
             embolism within 6 months before the first study drug administration.

          -  Those who have not recovered from adverse events due to agents administered more than
             4 weeks earlier.

          -  Concomitant therapy with the following medication is prohibited

               -  Concomitant use of strong inhibitors of CYP3A4 and strong inducers of CYP3A4 are
                  not permitted for 2 weeks prior to start of study treatment or during the study.

               -  Concomitant use of moderate and weak CYP3A4 inducers should be avoided as
                  clinically significant decrease in plasma concentrations of rogaratinib cannot be
                  ruled out.

               -  Concomitant use of herbal preparations containing CYP3A4 inducers (e.g. St John's
                  Wort) are not permitted during the study.

               -  Grapefruit and grapefruit juice (CYP3A4 inhibitor) consumption is not permitted
                  during the study.

               -  Therapies that are known to increase serum calcium or phosphate levels (i.e.
                  antacids, phosphate-containing laxatives oral/rectal, potassium phosphate)

               -  Patients may not receive other investigational treatment or other approved
                  anti-tumor therapy while on this protocol (excluding anti-VEGF therapy for
                  ophthalmologic disease).

          -  Concomitant therapies that should be avoided:

               -  Narrow therapeutic index drugs that are CYP3A4, P-gp, and BCRP substrates (e.g.
                  alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide,
                  quinidine, sirolimus, and tacrolimus) should be avoided, because drug
                  interactions caused by irreversible inhibition of CYP3A4, P-gp, and BCRP by
                  rogaratinib cannot be ruled out.

               -  Fluconazole is considered a moderate to strong inhibitor of CYP2C9 and should be
                  avoided, if possible.

               -  No results are available from human interaction studies between rogaratinib and
                  other chemotherapies. No data are available to evaluate the interaction between
                  rogaratinib and radiation. Therefore, when administering these agents after study
                  drug has been withdrawn, it should be taken into consideration that rogaratinib
                  plasma concentrations may be detectable for a few days (depending on half-life)
                  and the physiologic consequences that could interact with chemotherapy and
                  radiotherapy may last even longer following discontinuation of rogaratinib.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Response
Time Frame:6 months
Safety Issue:
Description:Absence of any cancer in the bladder (No carcinoma in situ or new lesions) on examination with TURBT

Secondary Outcome Measures

Measure:Duration of Response
Time Frame:2 years
Safety Issue:
Description:Duration of time from study entry until appearance of any cancer in the bladder (No carcinoma in situ or new lesions) on examination with TURBT
Measure:Rate Toxicity Occurs
Time Frame:2 years
Safety Issue:
Description:Percentage of patients with a side effect from rogaritinib while on study

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • Bladder Cancer

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