Clinical trial NCT02128282: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Cholangiocarcinoma
Keywords: Cholangiocarcinoma
Bile duct cancer
Biliary tract cancer
Lead sponsor: Senhwa Biosciences, Inc.
Sponsor class: INDUSTRY
First posted: 2014-05-01
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Primary outcomes:
measure: Maximum Tolerated Dose (MTD) of CX-4945 when used in combination with gemcitabine plus cisplatin. (Phase 1)
timeFrame: Cycle 1, 1 Full cycle up to twenty-one (21) days
measure: Comparison of the Progression-free survival (PFS) between the test and the control arms using Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 (Phase 2)
timeFrame: From date of randomization to date of progression or death from any cause up to 52 weeks.
measure: Recommended Phase II dose (RP2D) and schedule of CX-4945 in combination with gemcitabine plus cisplatin (Phase I)
timeFrame: Cycle 1, 1 Full cycle up to twenty-one (21) days
Secondary outcomes:
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
timeFrame: From date of randomization to date of progression or death from any cause up to 52 weeks.
measure: Comparison of the number of patient who transition to surgical resection
timeFrame: 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
measure: Comparison of the Overall Survival (OS) between the test and the control arms
timeFrame: From date of randomization to date of death from any cause up to 52 weeks.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic
state: Arizona
city: Aurora
country: United States
facility: University of Colorado- Denver
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Tyler
country: United States
facility: Texas Oncology-Tyler
state: Texas
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
state: Songpa-gu
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Kaohsiung City
country: Taiwan
facility: Chang-Gung Memorial Hospital - Kaohsiung Branch
city: Taichung City
country: Taiwan
facility: China Medical University Hospital
city: Tainan City
country: Taiwan
facility: National Cheng Kung University Hospitals
city: Taipei City
country: Taiwan
facility: National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taoyuan City
country: Taiwan
facility: Chang-Gung Memorial Hospital - Linkou Branch
Study officials:
affiliation: Mayo Clinic
name: Mitesh Borad, M.D.
role: PRINCIPAL_INVESTIGATOR
References: