A Japanese Phase 1 Trial of TH-302 in Subjects With Solid Tumors and Pancreatic Cancer

NCT01833546 | Completed Phase 1 Results

• 1 other identifier: EMR200592-002
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This is a Japanese Phase 1, open-label, and dose-escalating trial of TH-302 as monotherapy in subjects with solid tumors and in combination with gemcitabine in subjects with pancreatic cancer.

Conditions

Solid Tumor; Pancreatic Cancer

Keywords

Solid tumor; Pancreatic cancer; TH-302; Gemcitabine; Evofosfamide

Outcome Measures

Primary Outcomes (1)

• Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28

  A DLT was defined as any of the following toxicities at any dose level that occurred during the first cycle, and were considered to be related to the study drug by the Investigator or the Sponsor: - Grade 3 or Grade 4 non-hematological toxicity, except for Grade 3 or Grade 4 nausea, vomiting and diarrhea, - Grade 3 or higher skin reactions or mucosal toxicities, - Febrile neutropenia, - Grade 3 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation lasting more than 7 days, - Grade 4 neutropenia lasting more than 5 days, - Grade 4 thrombocytopenia, - Grade 4 anemia, - Any non-preexisting Grade 2 or higher non-hematologic toxicity which, in the judgment of the Investigator and the Sponsor, was considered a DLT, - Any Grade 2 or higher non-hematologic toxicity that did not resolve to Grade 0 or Grade 1 toxicity by the start of the next cycle which, in the judgment of the Investigator and the Sponsor, was considered a DLT.

  Day 1 up to Day 28 of Cycle 1

Secondary Outcomes (27)

• Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death

  Baseline up to 33 months

• Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

  Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15

• Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

  Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

• Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])

  Monotherapy: pre-dose, 0.25, 0.5, 0.58, 0.75, 1, 1.08, 1.25, 1.5, 2, 2.5, 3.5, 4.5, 6.5, 8.5, 12.5 hours post-dose on Day 1 and 15; Combination therapy: pre-dose, 0.5, 0.66, 1, 2, 2.5, 3, 3.5, 4, 4.5, 6.5, 8, 10.5, 26.5 hours post-dose on Day 1 and 15

• Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])

  Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15

Study Arms (4)

Evofosfamide 240 mg

EXPERIMENTAL

Drug: Evofosfamide

Evofosfamide 340 mg

EXPERIMENTAL

Drug: Evofosfamide

Evofosfamide 480 mg

EXPERIMENTAL

Drug: Evofosfamide

Evofosfamide 340 mg + Gemcitabine

EXPERIMENTAL

Drug: Evofosfamide; Drug: Gemcitabine

Interventions

Evofosfamide DRUG

Evofosfamide infusion intravenously at an escalated dose of 240, 340 or 480 milligram per square meter (mg/m\^2) on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or withdrawal.

Evofosfamide 240 mg; Evofosfamide 340 mg; Evofosfamide 340 mg + Gemcitabine; Evofosfamide 480 mg

Gemcitabine DRUG

Gemcitabine 1000 mg/m\^2 on Day 1, 8 and 15 of each 28-day treatment cycle until progressive disease, unacceptable toxicity or withdrawal.

Evofosfamide 340 mg + Gemcitabine

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• At least 20 years of age
• Signed written informed consent form
• Histologically or cytologically confirmed advanced or metastatic solid tumor previously treated with one or more standard treatment regimen(s) or for which no effective therapy is available
• Histologically or cytologically confirmed locally advanced unresectable or metastatic pancreatic adenocarcinoma previously untreated with chemotherapy or systemic therapy
• Recovered from toxicities of prior anti-cancer treatment to Grade 1 or less
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of at least 3 months
• Acceptable liver function, renal function, hematologic status and coagulation status as defined in the protocol
• No clinically significant abnormalities in urinalysis
• Effective contraception for both male and female subjects if the risk of conception exists

You may not qualify if:

• Prior anti-cancer treatment with more than 3 myelosuppressive cytotoxic chemotherapy regimens
• Prior treatment with gemcitabine for their advanced or metastatic pancreatic cancer, except for radiosensitizing doses of gemcitabine
• Prior radiotherapy to more than 30 percent of the bone marrow within 6 months prior to the trial entry
• Cardiac disease with New York Heart Association (NYHA) Class 3 or 4, within 6 months prior to the trial entry
• Clinically significant (that is, active) cardiovascular disease
• Seizure disorders requiring anticonvulsant therapy
• Known brain, leptomeningeal or epidural metastases (unless previously treated and well controlled for at least 3 months at the trial entry)
• Previously treated malignancies other than the current disease for at least 5 years at the trial entry
• Severe chronic obstructive or other pulmonary disease major surgery, within 4 weeks prior to the trial entry, without complete recovery
• Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
• Anti-cancer treatment prior to trial entry
• Participation in an investigational drug or device trial within 4 weeks prior to the trial entry
• Known infection with human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C
• A history of allergic reactions
• Taking a medication that is either moderate or strong inhibitor or inducer of cytochrome P450 (CYP)3A4 or is a sensitive substrate of other cytochrome P450

Sponsors & Collaborators

• Merck KGaA, Darmstadt, Germany: lead
• Threshold Pharmaceuticals: collaborator

Study Sites (2)

Research Site

Kashiwa, Japan

Location

Research Site

Tokyo, Japan

Location

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

TH 302; Gemcitabine

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Healthcare, a business of Merck KGaA, Darmstadt, Germany

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical Responsible

  Merck Serono Co., Ltd., Japan

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: April 12, 2013
• First Posted: April 17, 2013
• Study Start: April 18, 2013
• Primary Completion: August 31, 2015
• Study Completion: January 25, 2016
• Last Updated: October 15, 2018
• Results First Posted: October 15, 2018

Record last verified: 2018-02

Locations

JP (2)