Clinical Trials /

Study of CX-4945 in Combination With Gemcitabine and Cisplatin for Frontline Treatment of Cholangiocarcinoma

NCT02128282

Description:

This study considers the safety and tolerability of increasing doses of CX-4945 in combination with gemcitabine plus cisplatin to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D), followed by a randomized study that compares antitumor activity in cholangiocarcinoma patients receiving the standard of care gemcitabine plus cisplatin versus CX-4945 at the combination RP2D with gemcitabine plus cisplatin.

Related Conditions:
  • Cholangiocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of CX-4945 in Combination With Gemcitabine and Cisplatin for Frontline Treatment of Cholangiocarcinoma
  • Official Title: A Phase I/II Study of CX-4945 in Combination With Gemcitabine and Cisplatin in the Frontline Treatment of Patients With Cholangiocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: S4-13-001
  • NCT ID: NCT02128282

Conditions

  • Cholangiocarcinoma

Interventions

DrugSynonymsArms
CX-494510-day CX-4945 plus Cis/Gem
CisplatinPlatinol10-day CX-4945 plus Cis/Gem
GemcitabineGemzar10-day CX-4945 plus Cis/Gem

Purpose

This study considers the safety and tolerability of increasing doses of CX-4945 in combination with gemcitabine plus cisplatin to determine the maximum tolerated dose (MTD) and the recommended Phase II dose (RP2D), followed by a randomized study that compares antitumor activity in cholangiocarcinoma patients receiving the standard of care gemcitabine plus cisplatin versus CX-4945 at the combination RP2D with gemcitabine plus cisplatin.

Detailed Description

      Protein kinase CK2 is a constitutively active serine/threonine kinase with a long history as
      a pro-survival, anti-apoptotic kinase. Given the wide spread overexpression of CK2 in
      multiple cancers and its role in multiple non-oncogenic processes required to sustain the
      cancer phenotype, a selective inhibitor of CK2 is an attractive targeted approach to treating
      cancer.

      CX-4945 is a tetracyclic, small molecule carboxylate acid salt that exhibits potent and
      highly selective inhibition of CK2. Protein kinase CK2 is also known to play an important
      role in the DNA damage repair mechanisms of cancer cells, and this study of CX-4945 in
      combination with gemcitabine plus cisplatin will determine if inhibition of CK2, in
      conjunction with the use of chemotherapy drugs, will result in improved clinical outcomes for
      patients with non-resectable cholangiocarcinoma.
    

Trial Arms

NameTypeDescriptionInterventions
Escalation CX-4945 plus Cis/GemExperimentalCX-4945 capsules at the combination MTD on Days 0, 1 and 2, and Days 7, 8 and 9. PLUS Cisplatin 25 mg/m.sq. by IV infusion on Days 1 and 8. PLUS Gemcitabine 1,000 mg/m.sq. by IV infusion on Days 1 and 8. On a 21-day cycle.
  • CX-4945
  • Cisplatin
  • Gemcitabine
Cisplatin plus GemcitabineActive ComparatorCisplatin 25 mg/m.sq. by IV infusion on Days 1 and 8. PLUS Gemcitabine 1,000 mg/m.sq. by IV infusion on Days 1 and 8. On a 21-day cycle.
  • Cisplatin
  • Gemcitabine
10-day CX-4945 plus Cis/GemExperimentalCX-4945 capsules at 1000mg/BID, 10-day continuous dosing (Day 0 through Day 9). PLUS Cisplatin 25 mg/m.sq. by IV infusion on Days 1 and 8. PLUS Gemcitabine 1,000 mg/m.sq. by IV infusion on Days 1 and 8. On a 21-day cycle.
  • CX-4945
  • Cisplatin
  • Gemcitabine
21-day CX-4945 plus Cis/GemExperimentalCX-4945 capsules at 1000mg/BID, 21-day continuous dosing PLUS Cisplatin 25 mg/m.sq. by IV infusion on Days 1 and 8. PLUS Gemcitabine 1,000 mg/m.sq. by IV infusion on Days 1 and 8. On a 21-day cycle.
  • CX-4945
  • Cisplatin
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

          -  Presence of an unresectable hepatobiliary mass or metastatic disease (consistent with
             cholangiocarcinoma, as evidenced by histology or cytology (augmented by fluorescence
             in situ hybridization (FISH) where appropriate), for which treatment with gemcitabine
             plus cisplatin is intended. Intrahepatic and extrahepatic cholangiocarcinoma patients
             may be enrolled.

          -  For patients enrolled in the Dose Escalation Phase, one or more tumors measurable on
             radiograph or CT scan, or evaluable disease defined as non-measurable lesions per
             RECIST v. 1.1 (e.g., malignant ascites). All patients enrolled to the Randomized Study
             Phase must have measurable disease only.

          -  Laboratory data as specified below:

               -  Hematology: Absolute neutrophil count (ANC) >1,500 cells/mm3, platelet count
                  >100,000 cells/ mm.cu. and hemoglobin > 9 g/dL

               -  Hepatic: bilirubin <1.5 X Upper Limit of Normal (ULN); alkaline phosphatase
                  (ALP), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 5.0 X
                  ULN

               -  Renal: serum creatinine within normal limits (WNL), defined as within 25% of the
                  institution's stated reference range, or a calculated creatinine clearance >45
                  mL/min/1.73 m. sq. for patients with abnormal, increased, creatinine levels.

               -  Coagulation: International Normalized Ratio (INR) < 1.5 times normal, activated
                  Partial Thromboplastin Time (aPTT) < 1.5 times normal. Patients receiving
                  therapeutic doses of anticoagulant therapy may be considered eligible for the
                  trial if INR and aPTT are within the acceptable therapeutic limits for the
                  institution.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 1.

        Exclusion Criteria:

          -  A history of prior systemic treatment with gemcitabine or cisplatin. At least six
             months must have elapsed if gemcitabine or cisplatin was administered in an adjuvant
             treatment setting. Patients enrolled in the Expansion Cohort, Exploratory Cohorts, and
             the Randomized Phase must not have received prior systemic chemotherapies, including
             chemoradiation therapy for cholangiocarcinoma.

          -  Seizure disorders requiring anticonvulsant therapy.

          -  Known brain metastases (unless previously treated and well controlled for a period of
             at least 3 months).

          -  Major surgery other than diagnostic surgery, within 4 weeks prior to the first dose of
             test drug, minor surgery including diagnostic surgery within 2 weeks (14 days)
             excluding central IV port placements and needle aspirate/core biopsies. Radio
             frequency ablation or transcatheter arterial chemoembolization within 6 weeks prior to
             the first dose of test drug.

          -  Treatment with radiation therapy or surgery within one month prior to study entry.

          -  Treatment with chemotherapy or investigational drugs within 21 days prior to the
             screening visit. Acute toxicities from prior therapy must have resolved to Grade ≤ 1
             above baseline.

          -  Patients with a history of another malignancy within 3 years of the baseline visit.
             (Patients with cutaneous carcinomas or in-situ carcinomas will be considered for study
             entry on a case-by-case basis).

          -  Concurrent severe or uncontrolled medical disease (i.e., systemic infection, diabetes,
             hypertension, coronary artery disease, congestive heart failure).

          -  Active symptomatic fungal, bacterial and/or viral infection including active HIV or
             viral (A, B or C) hepatitis which would not permit the patient to be managed according
             to the protocol.

          -  Difficulty with swallowing or an active malabsorption syndrome.

          -  Chronic diarrhea (excess of 2-3 stools/day above normal frequency).

          -  Gastrointestinal diseases including ulcerative colitis, Crohn's disease, or
             hemorrhagic coloproctitis.

          -  History of gastric or small bowel surgery involving any extent of gastric or small
             bowel resection.

          -  Clinically significant bleeding event within the last 3 months, unrelated to trauma,
             or underlying condition that would be expected to result in a bleeding diathesis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) of CX-4945 when used in combination with gemcitabine plus cisplatin. (Phase 1)
Time Frame:Cycle 1, 1 Full cycle up to twenty-one (21) days
Safety Issue:
Description:The Maximum Tolerated Dose of CX-4945 will be determined from safety observations during the first cycle, as the CX-4945 dose is escalated in cohorts of three patients in combination with standard gemcitabine plus cisplatin.

Secondary Outcome Measures

Measure:Comparison of the Overall Response Rate (ORR) between the test and the control arms using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1
Time Frame:From date of randomization to date of progression or death from any cause up to 52 weeks.
Safety Issue:
Description:Tumor measurements will be compared to baseline, and the ORR will be determined using RECIST v. 1.1
Measure:Comparison of the number of patient who transition to surgical resection
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Safety Issue:
Description:The number of patients in the chemotherapy arm versus CX-4945 plus chemotherapy arm who transition to surgical resection will be compared.
Measure:Comparison of the Overall Survival (OS) between the test and the control arms
Time Frame:From date of randomization to date of death from any cause up to 52 weeks.
Safety Issue:
Description:Time to event is observed during treatment and followed up every 3 months after patient withdraw from treatment.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Senhwa Biosciences, Inc.

Trial Keywords

  • Cholangiocarcinoma
  • Bile duct cancer
  • Biliary tract cancer

Last Updated

November 10, 2020