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

NCT02128282 | Completed Phase 1 DMC

• 1 other identifier: S4-13-001
• Study Type: interventional
• Target: 127
• Locations: 3 countries
• Sites: 16

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.

Conditions

Cholangiocarcinoma

Keywords

Cholangiocarcinoma; Bile duct cancer; Biliary tract cancer

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose (MTD) of CX-4945 when used in combination with gemcitabine plus cisplatin. (Phase 1)

  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.

  Cycle 1, 1 Full cycle up to twenty-one (21) days

• 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)

  Tumor measurements will be compared to baseline every six weeks, and the PFS will be determined using RECIST v. 1.1.

  From date of randomization to date of progression or death from any cause up to 52 weeks.

• Recommended Phase II dose (RP2D) and schedule of CX-4945 in combination with gemcitabine plus cisplatin (Phase I)

  The recommended Phase II dose and schedule of CX-4945 will be determined from safety observations during the first cycle, as the CX-4945 dose is administered 1000mg BID in 10-day continuous or 21-day continuous cohorts in combination with standard gemcitabine plus cisplatin.

  Cycle 1, 1 Full cycle up to twenty-one (21) days

Secondary Outcomes (3)

• 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

  From date of randomization to date of progression or death from any cause up to 52 weeks.

• Comparison of the number of patient who transition to surgical resection

  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

• Comparison of the Overall Survival (OS) between the test and the control arms

  From date of randomization to date of death from any cause up to 52 weeks.

Study Arms (4)

Escalation CX-4945 plus Cis/Gem

EXPERIMENTAL

CX-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.

Drug: CX-4945; Drug: Cisplatin; Drug: Gemcitabine

Cisplatin plus Gemcitabine

ACTIVE COMPARATOR

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.

Drug: Cisplatin; Drug: Gemcitabine

10-day CX-4945 plus Cis/Gem

EXPERIMENTAL

CX-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.

Drug: CX-4945; Drug: Cisplatin; Drug: Gemcitabine

21-day CX-4945 plus Cis/Gem

EXPERIMENTAL

CX-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.

Drug: CX-4945; Drug: Cisplatin; Drug: Gemcitabine

Interventions

CX-4945 DRUG

API powder-in-capsule in 200 mg strength.

10-day CX-4945 plus Cis/Gem; 21-day CX-4945 plus Cis/Gem; Escalation CX-4945 plus Cis/Gem

Cisplatin DRUG

25 mg/m.sq. administered by IV infusion on Days 1 and 8 of a 21-day cycle.

Also known as: Platinol

10-day CX-4945 plus Cis/Gem; 21-day CX-4945 plus Cis/Gem; Cisplatin plus Gemcitabine; Escalation CX-4945 plus Cis/Gem

Gemcitabine DRUG

1,000 mg/m.sq. administered by IV infusion on Days 1 and 8 of a 21-day cycle.

Also known as: Gemzar

10-day CX-4945 plus Cis/Gem; 21-day CX-4945 plus Cis/Gem; Cisplatin plus Gemcitabine; Escalation CX-4945 plus Cis/Gem

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Senhwa Biosciences, Inc.: lead

Study Sites (16)

Mayo Clinic

Scottsdale, Arizona, 85259-5499, United States

Location

University of Colorado- Denver

Aurora, Colorado, 80045, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, 75246, United States

Location

Texas Oncology-Tyler

Tyler, Texas, 75702, United States

Location

Asan Medical Center

Seoul, Songpa-gu, 138-736, South Korea

Location

Samsung Medical Center

Seoul, South Korea

Location

Seoul National University Hospital

Seoul, South Korea

Location

Severance Hospital, Yonsei University Health System

Seoul, South Korea

Location

Chang-Gung Memorial Hospital - Kaohsiung Branch

Kaohsiung City, Taiwan

Location

China Medical University Hospital

Taichung, Taiwan

Location

National Cheng Kung University Hospitals

Tainan, Taiwan

Location

National Taiwan University Hospital

Taipei, Taiwan

Location

Taipei Veterans General Hospital

Taipei, Taiwan

Location

Chang-Gung Memorial Hospital - Linkou Branch

Taoyuan, Taiwan

Location

MeSH Terms

Conditions

Cholangiocarcinoma; Bile Duct Neoplasms; Biliary Tract Neoplasms

Interventions

silmitasertib; Cisplatin; Gemcitabine

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Mitesh Borad, M.D.

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2014
• First Posted: May 1, 2014
• Study Start: June 1, 2014
• Primary Completion: November 6, 2020
• Study Completion: August 5, 2021
• Last Updated: October 22, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

TW (6); US (6); KR (4)