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Testing TH-302, in Combination With Preoperative Chemoradiotherapy, in Esophageal Cancer.

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ClinicalTrials.gov Identifier: NCT02598687
Recruitment Status : Withdrawn (2 Phase 3 trials didn't meet their primary endpoint, so further development and testing of TH-302 is uncertain)
First Posted : November 6, 2015
Last Update Posted : April 21, 2016
Sponsor:
Collaborators:
Threshold Pharmaceuticals
Zuyderland Medical Centre
Information provided by (Responsible Party):
Maastricht Radiation Oncology

Brief Summary:
Open-label, single-center phase 1 study of an investigational agent TH-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels.

Condition or disease Intervention/treatment Phase
Esophageal Cancer Drug: TH-302 Other: HX4 scan Drug: Carboplatin Drug: Paclitaxel Radiation: Radiotherapy Procedure: surgery Phase 1

Detailed Description:

Rationale:

Neoadjuvant chemoradiotherapy followed by surgery remains the standard of care for esophageal cancer patients. Both limited local response as well as distant metastases are a common cause of treatment failure. Combining TH-302 with chemo-radiotherapy may improve outcome by:

  • Direct cytotoxic effect of TH-302 on hypoxic cells of the primary tumor without enhancing normal tissue toxicity.
  • Increase the sensitivity of the primary tumor to chemo-radiotherapy by decreasing the hypoxic fraction.
  • A bystander cytotoxic effect of TH-302 on normoxic cells adjacent to hypoxic cells of the primary tumor.
  • A potential cytotoxic effect on micro-metastasis.

Objective:

Primary objective

• To determine Maximum Tolerated Dose (MTD) of TH-302 combined with chemoradiotherapy (23 x 1.8 Gy in combination with Carboplatin and Paclitaxel) in patients with distal esophageal or esophago-gastric junction adenocarcinoma, and consequently find the recommended phase II dose (RP2D).

Secondary objective

  • To explore the prognostic and predictive value on outcome of the repeated hypoxia PET/CT-scan at baseline and after administration of TH-302 (before start of RCT).
  • To determine presence of anti-tumor activity with TH-302 administration.
  • To explore the relationship between tumor hypoxia detected by the HX4 PET/CT-scans and serum biomarker expression: CAIX and Osteopontin expression.

Study design: Open-label, single-center phase 1 study of an investigational agent TH-302 and standard chemoradiotherapy with a 3+3 dose escalation design through 3 dose levels.

Number of patients: 9 to18. For each of the 3 dose steps, 3 to 6 patients will be included.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial Testing TH-302, a Tumor-selective Hypoxia-Activated Cytotoxic Prodrug, in Combination With Preoperative Chemoradiotherapy in Patients With Distal Esophageal and Esophago-gastric Junction Adenocarcinoma
Study Start Date : December 2015
Actual Primary Completion Date : April 2016
Actual Study Completion Date : April 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
treatment
treatment arm: TH-302 pre-treatment day 4 and weekly during treatment. 5 x carboplatin and paclitaxel, radiotherapy: 23 x 1.8Gy HX4 scans day 1 and day 8,surgery 6-10 weeks after chemo-radiotherapy
Drug: TH-302
TH-302 day 4 (pre-treatment) and weekly during chemo-radiotherapy (CRT)

Other: HX4 scan
HX 4 scan day 1 and day 8

Drug: Carboplatin
2mg/ml/min

Drug: Paclitaxel
50 mg/m2

Radiation: Radiotherapy
23 x 1.8 Gy

Procedure: surgery
minimally invasive transhiatal approach including a one-field node dissection or transthoracic approach with a two-field lymph node dissection




Primary Outcome Measures :
  1. Dose Limiting Toxicity (DLT ) [ Time Frame: within 30days postoperative ]
    To determine the DLT and define the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)


Secondary Outcome Measures :
  1. hypoxia response in tumor [ Time Frame: day 4 and day 8 ]
    Presence of hypoxia response based on hypoxia imaging (HX4) at baseline and first administration of TH-302 (before chemoradiotherapy).

  2. rate of pathological Complete Remission (pCR) [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by the rate of pathological Complete Remission (pCR)

  3. histopathologic negative circumferential resection margin (CRM) rate [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by histopathologic negative circumferential resection margin (CRM) rate.

  4. Local recurrence rate [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by local recurrence rate

  5. distance recurrence rate [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by distance recurrence rate

  6. Progression free survival [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by progression free survival

  7. overall survival [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by overall survival

  8. metabolic response [ Time Frame: within 30 days after surgery ]
    Presence of anti-tumor activity measured by metabolic response one month after treatment



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically proven adenocarcinoma of the esophagus
  • Age >18 years
  • UICC T2-4 N0-2 M0, potentially resectable disease
  • Patient discussed at tumour board (multidisciplinary team meeting)
  • No evident tumor invasion in nearby regions like aorta or trachea
  • WHO performance status 0-2
  • Less than 10 % weight loss in the past 6 months
  • Laboratory requirements within 7 days prior to enrollment (start chemoradiotherapy):
  • Haematology:

    • haemoglobin >10g/dl
    • absolute neutrophils ≥ 1.5 x 109/L
    • platelets ≥ 100x109/L
  • Biochemistry:

    • bilirubin within institutional normal limits
    • AST(SGOT)/ALT (SGPT) ≤ 2.5 institutional upper limit
    • Creatinine clearance ≥ 60 ml/min
  • Willing and able to comply with the study prescriptions
  • No history of prior thoracic radiotherapy
  • No severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
  • Women should not be pregnant or lactating
  • No known infection with HIV, hepatitis B or C or any other active infection
  • Normal ECG with careful evaluation of QT/QTc
  • Have given written informed consent before patient registration

Exclusion Criteria:

  • Recent (< 3 months) severe cardiac disease (arrhythmia, congestive heart failure, infarction)
  • Patients with difficult peripheral intravenous access
  • History of prior thoracic radiotherapy
  • severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia
  • Women who are pregnant or lactating
  • Known infection with HIV, hepatitis B or C or any other active infection

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 ClinicalTrials.gov identifier (NCT number): NCT02598687


Sponsors and Collaborators
Maastricht Radiation Oncology
Threshold Pharmaceuticals
Zuyderland Medical Centre
Investigators
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Principal Investigator: Philippe Lambin, MD, PhD MUMC+, dept Radiotherapy

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Maastricht Radiation Oncology
ClinicalTrials.gov Identifier: NCT02598687     History of Changes
Other Study ID Numbers: 14-27-03/09
First Posted: November 6, 2015    Key Record Dates
Last Update Posted: April 21, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Esophageal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Head and Neck Neoplasms
Digestive System Diseases
Esophageal Diseases
Gastrointestinal Diseases
Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action