A Japanese Trial of TH-302 in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02255110
Recruitment Status : Terminated (Sponsor's decision due to negative result of Phase 3 study TH-CR-406/SARC021)
First Posted : October 2, 2014
Last Update Posted : June 17, 2016
Threshold Pharmaceuticals
Information provided by (Responsible Party):
Merck KGaA

Brief Summary:
This is a Phase 2, single-arm, Japanese multicenter trial to evaluate the safety, tolerability, and efficacy of TH-302 in combination with doxorubicin in subjects with locally advanced unresectable or metastatic soft tissue sarcoma (STS).

Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Drug: TH-302 Drug: Doxorubicin Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II, Single-arm, Japanese Multicenter Trial of TH-302 in Combination With Doxorubicin in Subjects With Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma
Study Start Date : December 2014
Actual Primary Completion Date : January 2016
Actual Study Completion Date : January 2016

Arm Intervention/treatment
Experimental: TH-302 and doxorubicin Drug: TH-302
TH-302 will be administered at a dose of 300 milligram per square meter (mg/m^2) by intravenous infusion over 30 minutes on Days 1 and 8 of every 21-day cycle until the evidence of significant treatment-related toxicity or progressive disease.

Drug: Doxorubicin
Doxorubicin will be administered at a dose of 75 mg/m^2 by intravenous injection (over at least 5 minutes) or by intravenous infusion over 6-96 hours on Day 1 of every 21-day cycle starting 2 to 4 hours after completion of TH-302 administration until the evidence of significant treatment-related toxicity or progressive disease.

Primary Outcome Measures :
  1. Percentage of Subjects with Progression-free Survival (PFS) at 6 months: independent-read assessment [ Time Frame: 6 months ]
    Percentage of Subjects with Progression-free Survival (PFS) is defined as the treated subjects without progression or occurrence of death due to any cause. PFS is defined as time from first dose to either first observation of progressive disease (PD) (according to Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1) or occurrence of death due to any cause up to 63 days following the last response assessment (or from start of treatment for subjects without a response assessment), whichever occurs first. In subjects without a progression date or with a death date more than 63 days after the last tumor assessment, the PFS time will be censored on the date of last tumor assessment. Subjects with no tumor assessment available and who have neither progressed nor died will be censored on the day of start of therapy. PFS rate will be assessed using Kaplan Meier method.

Secondary Outcome Measures :
  1. Percentage of Subjects with Progression-free Survival (PFS) at 6 months: investigator-read assessment [ Time Frame: 6 months ]
  2. Percentage of Subjects with Progression-free Survival (PFS) at 3 and 9 months: independent- and investigator-read assessment [ Time Frame: 3 and 9 months ]
  3. Percentage of Subjects with Overall Response [ Time Frame: Up to 1 year ]
    The overall response is defined as achieving complete response (CR) or partial response (PR) as the best overall response according to RECIST Version 1.1. CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to less than (<) 10 millimeter (mm). PR is defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  4. Duration of Response [ Time Frame: Up to 1 year ]
    The duration of response is defined as time from date of first response to date of disease progression (according to RECIST Version 1.1) or death, estimated using the Kaplan-Meier method.

  5. Percentage of Subjects with 12-month Survival [ Time Frame: Up to 12 months after last subject's first dose ]
    The overall survival (OS) is defined (in months) as the time from start of therapy to occurrence of death due to any cause: (date of death or last date known to be alive - date of start of therapy + 1) / 30.4375. For subjects not known to be deceased at time of analysis, the time between the date of start of therapy and date of last contact or date lost to follow-up will be calculated and used as a censored observation in the analysis. If this date is after the data cut-off, subjects will be censored at the date of data cut-off.

  6. Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 30 days post-last administration of study drug ]

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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male or female Japanese subjects greater than or equal to (>=) 15 years of age
  • Able to understand the purposes and risks of the trial and has signed or, if appropriate, the subject's parent or legal guardian has signed a written informed consent form approved by the Institutional Review Board (IRB) or Independent Ethics Committee (IEC)
  • Pathologically confirmed diagnosis of STS of the histopathologic types as specified in the protocol
  • Locally advanced unresectable or metastatic disease with no standard curative therapy available and for whom treatment with single agent doxorubicin is considered appropriate
  • Recovered from reversible toxicities of prior therapy
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (at least one target lesion outside of previous radiation fields or progressed within a previous radiation field)
  • 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 (without growth factor support for neutropenia or transfusion dependency), and cardiac function as specified in the protocol
  • All women of childbearing potential must have a negative serum pregnancy test and all subjects must agree to use effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an intrauterine device, intrauterine device [IUD]) with their partner from entry into the trial through 6 months after the last dose. Post-menopausal women must meet the criteria of 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels greater than (>) 35 international units per liter (IU/L)

Exclusion Criteria:

  • Low grade tumors according to standard grading systems (for example, American Joint Committee on Cancer [AJCC] Grade 1 and 2 or Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] Grade 1)
  • Prior systemic therapy for advanced or metastatic STS (neoadjuvant therapy followed by surgical resection and adjuvant therapy permitted)
  • Prior STS therapy with ifosfamide or cyclophosphamide or other nitrogen mustards; prior systemic therapy with an anthracycline or anthracenedione; or prior mediastinal/cardiac radiotherapy
  • Current use of drugs with known cardiotoxicity or known interactions with doxorubicin
  • Anti-cancer treatment with radiation therapy, neoadjuvant or adjuvant chemotherapy, targeted therapies, immunotherapy, hormones or other antitumor therapies within 4 weeks prior to trial entry (6 weeks for nitrosoureas or mitomycin C).
  • Significant cardiac dysfunction precluding treatment with doxorubicin as specified in the protocol
  • Seizure disorders requiring anticonvulsant therapy unless seizure-free for the last year
  • Known brain metastases (unless previously treated and well controlled for a period of >=3 months before screening)
  • Previously diagnosed malignancies, except for adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 5 years before screening
  • Severe chronic obstructive or other pulmonary disease with hypoxemia (requires supplementary oxygen, symptoms due to hypoxemia or oxygen saturation <90% by pulse oximetry after a 2 minute walk) or in the opinion of the investigator any physiological state likely to cause normal tissue hypoxia
  • Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery
  • Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy
  • Prior therapy with a hypoxic cytotoxin
  • Subjects who participated in an investigational drug or device trial within 28 days prior to trial entry
  • Known infection with human immunodeficiency virus (HIV) or active infection with hepatitis B or hepatitis C
  • Subjects who have exhibited allergic reactions to a structural compound similar to TH-302 or the drug product excipients
  • Subjects who are taking medications that prolong QT interval and have a risk of Torsades de Pointes
  • Subjects with a corrected QT (QTc) interval calculated according to Bazett's formula of >450 milliseconds (msec) based on a screening electrocardiogram (ECG)
  • Subjects with a history of long QT syndrome
  • Subjects taking a medication that is a moderate or strong inhibitor or inducer of cytochrome P450 3A4 (CYP3A4)
  • Females who are pregnant or breast-feeding
  • Concomitant disease or condition that could interfere with the conduct of the study, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study
  • Unwillingness or inability to comply with the study protocol for any reason
  • Legal incapacity or limited legal capacity

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02255110

Research Site
Kashiwa, Japan
Research Site
Tokyo, Japan
Sponsors and Collaborators
Merck KGaA
Threshold Pharmaceuticals
Study Director: Medical Responsible Merck Serono Co., Ltd., Japan

Responsible Party: Merck KGaA Identifier: NCT02255110     History of Changes
Other Study ID Numbers: EMR200592-008
First Posted: October 2, 2014    Key Record Dates
Last Update Posted: June 17, 2016
Last Verified: June 2016

Keywords provided by Merck KGaA:
Locally Advanced Unresectable or Metastatic Soft Tissue Sarcoma

Additional relevant MeSH terms:
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Liposomal doxorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action