Clinical trial NCT01833546: A Japanese Phase 1 Trial of TH-302 in Subjects With Solid Tumors and Pancreatic Cancer
Official title: A Japanese Single Center, Open-label, Phase I Trial of TH-302 Given Intravenously to Subjects With Solid Tumors as Monotherapy or to Subjects With Advanced Pancreatic Cancer in Combination With Gemcitabine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumor
Pancreatic Cancer
Keywords: Solid tumor
Pancreatic cancer
TH-302
Gemcitabine
Evofosfamide
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Threshold Pharmaceuticals
First posted: 2013-04-17
Enrollment: 20
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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
* Other inclusion criteria apply

Exclusion Criteria:

* 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
* Pregnancy or lactation period
* Concomitant disease or condition that could interfere with the conduct of the trial, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this trial
* Unwillingness or inability to comply with the trial protocol for any reason
* Legal incapacity or limited legal capacity
* Other exclusion criteria apply

Primary outcomes:
measure: Number of Participants Who Experienced Any Dose-Limiting Toxicity (DLT) During First Cycle - Day 1 to 28
timeFrame: Day 1 up to Day 28 of Cycle 1
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAE), Serious TEAEs, TEAEs Leading to Death
timeFrame: Baseline up to 33 months
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])
timeFrame: 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
measure: Time to Reach Maximum Plasma Concentration (Tmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Maximum Observed Plasma Concentration (Cmax) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])
timeFrame: 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
measure: Terminal Rate Constant Associated With the Terminal Elimination Phase (λz) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Apparent Terminal Half-life (t1/2) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])
timeFrame: 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
measure: Apparent Terminal Half-life (t1/2) of of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Sampling Time With Concentration at or Above the Lower Limit of Quantitation (AUC[0-t]) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Sampling Time With Concentration at or Above the Lower Limit of Quantitation (AUC[0-t]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Evofosfamide and Its Metabolite (Bromo-isophosphoramide Mustard [Br-IPM])
timeFrame: 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
measure: Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC [0-infinity]) of Gemcitabine and Its Metabolite (2',2'-Difluorodeoxyuridine [dFdU])
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Apparent Total Body Clearance of (CL) of Evofosfamide
timeFrame: 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
measure: Apparent Total Body Clearance of (CL) of Gemcitabine
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Apparent Volume of Distribution at Steady State (Vss) of Evofosfamide
timeFrame: 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
measure: Apparent Volume of Distribution at Steady State (Vss) of Gemcitabine
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Apparent Volume of Distribution During Terminal Phase (Vz) of Evofosfamide
timeFrame: 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
measure: Apparent Volume of Distribution During Terminal Phase (Vz) of Gemcitabine
timeFrame: Pre-dose, 0.5, 1, 2, 4, 8, and 24 hours post-dose on Day 1 and 15
measure: Cumulative Amount of Evofosfamide Excreted From Time Zero to Time After Dosing (Ae0-t)
timeFrame: 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
measure: Renal Clearance (CL) for Evofosfamide
timeFrame: 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
measure: Best Overall Response (BOR)
timeFrame: Time from first treatment to final assessment at 33 months
measure: Number of Participants With Objective Response
timeFrame: Time from first treatment to final assessment at 33 months
measure: Number of Participants With Disease Control
timeFrame: Time from first treatment to final assessment at 33 months
measure: Number of Participants With Clinical Significant Laboratory Abnormalities and Vital Signs Abnormalities Reported as Treatment Emergent Adverse Events
timeFrame: Baseline up to 33 months
measure: Number of Participants With Abnormal Electrocardiogram (ECG) Findings Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: Baseline up to 33 months
measure: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status Score of 2 or Higher Than 2
timeFrame: Baseline up to 33 months
Other outcomes:
Locations:
city: Kashiwa
country: Japan
facility: Research Site
city: Tokyo
country: Japan
facility: Research Site
Study officials:
affiliation: Merck Serono Co., Ltd., Japan
name: Medical Responsible
role: STUDY_DIRECTOR
References: