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Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, the RadiCaL Study

NCT04071223

Description:

This phase II trial studies whether adding radium-223 dichloride to the usual treatment, cabozantinib, improves outcome in patients with renal cell cancer that has spread to the bone. Radioactive drugs such as radium-223 dichloride may directly target radiation to cancer cells and minimize harm to normal cells. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving radium-223 dichloride and cabozantinib may help lessen the pain and symptoms from renal cell cancer that has spread to the bone, compared to cabozantinib alone.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of a New Anti-cancer Drug, Radium-223 Dichloride, to the Usual Treatment (Cabozantinib) for Advanced Renal Cell Cancer That Has Spread to the Bone, the RadiCaL Study
  • Official Title: A Phase II Randomized Trial of Radium-223 Dichloride and Cabozantinib in Patients With Advanced Renal Cell Carcinoma With Bone Metastasis (RadiCal)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-05619
  • SECONDARY ID: NCI-2019-05619
  • SECONDARY ID: A031801
  • SECONDARY ID: A031801
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04071223

Conditions

  • Advanced Renal Cell Carcinoma
  • Chromophobe Renal Cell Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Collecting Duct Carcinoma
  • Kidney Medullary Carcinoma
  • Metastatic Malignant Neoplasm in the Bone
  • Papillary Renal Cell Carcinoma
  • Stage IV Renal Cell Cancer AJCC v8
  • Unclassified Renal Cell Carcinoma

Interventions

DrugSynonymsArms
CabozantinibArm A (radium Ra 223 dichloride, cabozantinib s-malate)
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Arm A (radium Ra 223 dichloride, cabozantinib s-malate)

Purpose

This phase II trial studies whether adding radium-223 dichloride to the usual treatment, cabozantinib, improves outcome in patients with renal cell cancer that has spread to the bone. Radioactive drugs such as radium-223 dichloride may directly target radiation to cancer cells and minimize harm to normal cells. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving radium-223 dichloride and cabozantinib may help lessen the pain and symptoms from renal cell cancer that has spread to the bone, compared to cabozantinib alone.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the symptomatic skeletal event (SSE)-free survival of metastatic renal cell
      cancer (mRCC) patients with bone metastases treated with cabozantinib S-malate (cabozantinib)
      + radium Ra 223 dichloride (radium-223 dichloride) compared to cabozantinib alone.

      SECONDARY OBJECTIVES:

      I. To investigate the safety, toxicity and tolerability as defined by Common Terminology
      Criteria for Adverse Events (CTCAE) version 5.0 in patients treated with cabozantinib +
      radium-223 dichloride compared to cabozantinib alone.

      II. To assess SSE-free survival of each treatment arm in predefined sub-groups. III. To
      assess progression-free survival (PFS) in each treatment arm. IV. To assess overall survival
      (OS) in each treatment arm. V. To assess time to first SSE (defined as first use of radiation
      therapy to relieve skeletal symptoms, new symptomatic pathologic vertebral or non-vertebral
      bone fractures, spinal cord compression, or symptomatic tumor-related orthopaedic surgical
      intervention) in each treatment arm.

      VI. To assess the objective response rate by Response Evaluation Criteria in Solid Tumors
      (RECIST) version 1.1.

      EXPLORATORY QUALITY OF LIFE OBJECTIVES:

      I. To compare patient-reported pain as assessed by the Brief Pain Inventory questionnaire
      (BPI) between patients randomized to cabozantinib versus cabozantinib + radium-223 dichloride
      at 6 months.

      II. To compare patient-reported pain as assessed by the BPI between patients randomized to
      cabozantinib versus cabozantinib + radium-223 dichloride at other timepoints.

      III. To compare overall health-related quality of life as assessed by the Patient-Reported
      Outcomes Measurement Information Systems (PROMIS) Global Health 10 between patients
      randomized to cabozantinib versus cabozantinib + radium-223 dichloride.

      IV. To compare quality-adjusted survival (overall survival x utility score assessed by
      European Quality of Life Five Dimension Five Level Scale [EQ5D-5L]) between patients
      randomized to cabozantinib + radium-223 dichloride.

      CORRELATIVE OBJECTIVES:

      I. To evaluate changes in the following bone turnover markers between arms:

      Ia. Marker of bone formation: P1NP, BSAP. Ib. Marker of bone resorption: CTX, NTX. II. To
      correlate changes in bone turnover markers with SSE-free survival. III. To assess the
      immunomodulatory properties of cabozantinib with or without radium-223 dichloride at
      baseline, during treatment, and at progression.

      IV. To identify prognostic and predictive genomic biomarkers of response to cabozantinib and
      radium-223 dichloride via assessment of tissue, circulating tumor cells (CTCs) and
      circulating tumor deoxyribonucleic acid (DNA) (cfDNA).

      V. To assess the association between bone response according to MD Anderson response criteria
      and SSE-free survival (FS).

      VI. To correlate change in level of total alkaline phosphatase and bone-specific alkaline
      phosphatase to overall response to cabozantinib + radium-223 dichloride compared to
      cabozantinib alone.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive radium Ra 223 dichloride intravenously (IV) over 1 minute on day 1 of
      cycles 1-6 and cabozantinib S-malate orally (PO) once daily (QD) on days 1-28 of every cycle.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for up to 5
      years from study registration.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (radium Ra 223 dichloride, cabozantinib s-malate)ExperimentalPatients receive radium Ra 223 dichloride IV over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate PO QD on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate
Arm B (cabozantinib s-malate)Active ComparatorPatients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate

Eligibility Criteria

        Inclusion Criteria:

          -  Documented histologic or cytologic diagnosis of renal cell cancer (RCC). All subtypes
             of RCC are eligible including but not limited to clear cell, papillary, chromophobe,
             translocation, collecting duct carcinoma, medullary carcinoma, and unclassified
             categories. Enrollment of non-clear cell patients will be limited to 20% of the total
             sample size (~ 42 patients). Once this goal is met, accrual of non-clear cell patients
             will be discontinued (a notice will be sent out 2 weeks in advance). Sarcomatoid and
             rhabdoid differentiation are allowed

          -  Presence of at least 2 metastatic bone lesions not treated with prior radiation is
             required

               -  The presence of bone metastases can be detected by computed tomography (CT),
                  magnetic resonance imaging (MRI), Tc-99m bone scan or positron emission
                  tomography (PET) (fludeoxyglucose F-18 [FDG] or sodium fluoride [NaF]) imaging.
                  Patients with non-measurable bone-only disease are allowed. Patients may have
                  received prior radiation therapy for bone metastases or other external radiation
                  >= 14 days prior to registration, as long as they still have at least 2
                  metastatic bone lesions that were not treated with radiation. Patients with
                  visceral metastases are allowed, as long as they have at least two untreated bone
                  metastases

          -  No more than 2 prior lines of systemic therapy including but not limited to
             anti-angiogenic therapy, checkpoint inhibitors, mammalian target of rapamycin (mTOR)
             inhibitors, clinical trial compounds or cytokine-based therapy. Prior radiation
             therapy does not count as a prior systemic therapy

          -  No prior treatment with cabozantinb

          -  No treatment with any type of small molecular kinase inhibitor (including
             investigational kinase inhibitors) within 2 weeks or 5 half-lives (whichever is
             shorter) of registration or receipt of any anti-cancer therapy (including
             investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of
             registration

          -  No prior hemibody external radiotherapy

          -  No prior therapy with radium-223 dichloride or systemic radiotherapy (such as
             samarium, strontium)

          -  No major surgery within 6 weeks of randomization. Procedures such as thoracentesis,
             paracentesis, percutaneous biopsy, Moh's or other topical skin surgery, Lasik eye
             surgery are not considered major surgery. Patients who have had a nephrectomy may be
             registered >= 3 weeks after surgery, providing there are no wound-healing
             complications. Subjects with clinically relevant ongoing complications from prior
             surgery are not eligible

          -  Recovery to baseline or =< grade 1 CTCAE version 5.0 from toxicity related to any
             prior treatment, unless adverse events are clinically nonsignificant and/or stable on
             supportive therapy

          -  The use of osteoclast targeted therapy including either bisphosphonates or denosumab
             is mandated on this study except in patients with contraindications as determined by
             the treating investigator, including:

               -  Hypocalcemia

               -  Hypophosphatemia

               -  Renal impairment including those with a glomerular filtration rate (GFR) < 35
                  mL/min using the Cockcroft-Gault equation or acute renal impairment

               -  Hypersensitivity to drug formulation

                    -  Dental condition or need for dental intervention that per the investigator
                       would increase the risk of osteonecrosis of jaw (ONJ).

                    -  Use of osteoclast targeted therapy or reason against use needs to be
                       recorded in the electronic case report form (eCRF). Additionally, reason for
                       discontinuation of osteoclast targeted therapy need to be appropriately
                       documented in the eCRF

          -  Not pregnant and not nursing, because this study involves an investigational agent
             whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn
             are unknown.

               -  Therefore, for women of childbearing potential only, a negative urine pregnancy
                  test done =< 28 days prior to registration is required. A female of childbearing
                  potential is a sexually mature female who: 1) has not undergone a hysterectomy or
                  bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least
                  12 consecutive months (i.e., has had menses at any time in the preceding 12
                  consecutive months)

          -  Karnofsky performance status >= 60%

          -  Symptomatic bone pain defined as either regular use of analgesic medication for cancer
             related bone pain (>= level 1; World Health Organization [WHO] ladder for cancer pain)
             or prior SSE defined as bone pain requiring radiation, bone pain secondary to a
             pathologic fracture related to a bone metastasis, symptomatic spinal cord compression
             related to a bone metastasis, surgery to bone secondary to symptomatic bone metastasis
             or radiographic progression of bone metastases as defined by the presence of bone
             metastases on radiographic imaging

          -  No brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to
             registration as documented by MRI or CT imaging or deemed stable by clinical
             investigator. Treated brain metastases are defined as having no ongoing requirement
             for steroids and no evidence of progression or hemorrhage after treatment for at least
             4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by
             clinical investigator

          -  No imminent or established spinal cord compression based on clinical symptoms and/or
             imaging. In patients with untreated imminent or established spinal cord compression,
             treatment with standard of care as clinically indicated should be completed at least 2
             weeks before registration

          -  No imminent or impending pathologic fracture based on clinical symptoms and/or
             imaging. In patients with untreated imminent or impending pathologic fracture,
             treatment with standard of care as clinically indicated should be completed at least 2
             weeks before registration

          -  No significant, uncontrolled intercurrent or recent illness, including but not limited
             to the following conditions:

               -  Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina
                  pectoris, serious cardiac arrhythmia; uncontrolled hypertension defined as
                  sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite
                  optimal antihypertensive treatment; stroke (including transient ischemic attack),
                  myocardial infarction, or other ischemic event, within 6 months before
                  randomization; thromboembolic event (e.g., deep venous thrombosis, pulmonary
                  embolism) within 1 month before randomization; screening Fridericia's correction
                  formula (QTcF) =< 500 msec

               -  Gastrointestinal disorders: Disorders associated with a high risk of perforation
                  or fistula formation: active inflammatory bowel disease, active diverticulitis,
                  active cholecystitis, active symptomatic cholangitis or active appendicitis,
                  active acute pancreatitis or active acute obstruction of the pancreatic or
                  biliary duct, or active gastric outlet obstruction; abdominal fistula,
                  gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess
                  within 3 months before randomization. Note: Complete healing of an
                  intra-abdominal abscess must be confirmed before randomization

               -  No clinically significant hematuria, hematemesis, or hemoptysis, or other history
                  of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before
                  randomization

               -  No lesions invading major pulmonary blood vessels

               -  No other clinically significant disorders:

                    -  Human immunodeficiency virus (HIV)-infected patients on effective
                       anti-retroviral therapy (with no medications prohibited by this protocol
                       [e.g. drug-drug interactions]) with undetectable viral load within 6 months
                       are eligible for this trial

                    -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the
                       HBV viral load must be undetectable on suppressive therapy (with no
                       medications prohibited by this protocol [e.g. drug-drug interactions]), if
                       indicated

                    -  Patients with a history of hepatitis C virus (HCV) infection must have been
                       treated and cured. For patients with HCV infection who are currently on
                       treatment, they are eligible if they have an undetectable HCV viral load
                       (with no medications prohibited by this protocol [e.g. drug-drug
                       interactions])

                    -  No serious non-healing wound or ulcer

                    -  No malabsorption syndrome

                    -  No uncompensated/symptomatic hypothyroidism

                    -  No moderate to severe hepatic impairment (Child-Pugh B or C)

                    -  No requirements for hemodialysis or peritoneal dialysis

                    -  No history of solid organ transplantation

          -  No chronic concomitant treatment with strong CYP3A4 inducers or inhibitors. Because
             the list of these agents is constantly changing, it is important to regularly consult
             a frequently updated medical reference. Patients may not have received a strong CYP3A4
             inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7
             days prior to registration

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3

          -  Platelet count >= 100,000/mm^3

          -  Hemoglobin >= 10 g/dl (transfusions allowed)

          -  Calculated (calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault
             equation

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN), for patients with Gilberts
             disease =< 3.0 x ULN

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN

          -  Urine protein to creatinine (UPC) ratio =< 1 mg/mg OR 24-hr urine protein < 1g
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Symptomatic skeletal event (SSE)-free survival (FS)
Time Frame:From the date of randomization to the date of the earliest occurrence of SSE or death from any cause, assessed up to 5 years
Safety Issue:
Description:SSE-FS distribution will be estimated using the method of Kaplan-Meier by treatment arm. Comparison between the two arms will be performed using a one-sided log-rank test and one-sided p-value less than 0.025 will indicate that the experimental arm is superior to the control arm. SSE-FS will be censored at the date of last SSE assessment for those alive and SSE free. Hazard ratio (experimental over control arm) as well as two-sided 90% confidence interval (CI) for treatment will be estimated using the stratified Cox proportional hazard model with a single treatment covariate.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:Will be determined using Common Terminology Criteria for Adverse Events version 5.0. Adverse events will be summarized and compared between arms using chi-square or fisher exact tests as appropriate.
Measure:SSE-FS
Time Frame:From randomization to the date of SSE or death due to any cause, whichever comes first, assessed up to 5 years
Safety Issue:
Description:Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test.
Measure:Progression-free survival
Time Frame:From randomization to time of radiographic progression or death due to any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Radiographic progression will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test.
Measure:Overall survival
Time Frame:From randomization to the date of death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be estimated with the Kaplan Meier methodology. Comparison between arms or between predefined groups will be conducted using the log-rank test. Patients who are alive will be censored at last follow up date.
Measure:Time to first SSE
Time Frame:From randomization to the date of first SSE or death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be determined in each treatment. The median estimate to first SSE-FS will be calculated.
Measure:Overall response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined by RECIST version 1.1. Number and proportion of patients achieving ORR (by RECIST) will be summarized with two-sided 90% CI by treatment arm; comparison between arms will be conducted using chi-square or Fisher's exact test as appropriate.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

March 9, 2020