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A Study Evaluating Safety and Therapeutic Activity of THOR-707 in Adult Subjects With Advanced or Metastatic Solid Tumors (THOR-707-101)

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ClinicalTrials.gov Identifier: NCT04009681
Recruitment Status : Recruiting
First Posted : July 4, 2019
Last Update Posted : July 29, 2019
Sponsor:
Information provided by (Responsible Party):
Synthorx, Inc.

Brief Summary:
This is an open-label, First-in-Human, dose escalation and dose expansion study of THOR-707 (Monotherapy and Combination Therapy) in adult subjects with advanced or metastatic solid tumors.

Condition or disease Intervention/treatment Phase
Solid Tumor, Unspecified, Adult Drug: THOR-707 Drug: Checkpoint inhibitor Phase 1 Phase 2

Detailed Description:
This is a First-in-Human, open-label, multiple ascending dose escalation and dose expansion study of THOR-707 in adult subjects with advanced or metastatic solid tumors. The objectives of the dose escalation phase are to identify the recommended phase 2 dose (RP2D) of THOR-707 as a monotherapy (Part 1) and in combination with a checkpoint inhibitor (Part 2); to evaluate safety/tolerability of THOR-707; to evaluate anti-tumor activity of THOR-707; to evaluate pharmacokinetics of THOR-707; and to evaluate various immunological biomarkers pre- and post-treatment with THOR-707. The objectives of the dose expansion phase (Part 3) are to further evaluate safety and anti-tumor activity of THOR-707 (administered at the RP2D) as a monotherapy and in combination with a checkpoint inhibitor in select populations of patients with advanced or metastatic solid tumors.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 300 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter Phase 1/2 Dose Escalation and Expansion Study of THOR-707 as a Single Agent and in Combination With a Checkpoint Inhibitor in Adult Subjects With Advanced or Metastatic Solid Tumors
Actual Study Start Date : June 20, 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2022

Arm Intervention/treatment
Experimental: THOR-707 Monotherapy, Q2W
Dose Escalation: THOR-707 will be administered in sequential ascending doses as a monotherapy via intravenous (IV) administration every 2 weeks (Q2W) until unacceptable toxicity, disease progression, or withdrawal of consent.
Drug: THOR-707
THOR-707 will be administered as specified under Arm description.

Experimental: THOR-707 Monotherapy, Q3W
Dose Escalation: THOR-707 will be administered in sequential ascending doses as a monotherapy via IV administration every 3 weeks (Q3W) until unacceptable toxicity, disease progression, or withdrawal of consent.
Drug: THOR-707
THOR-707 will be administered as specified under Arm description.

Experimental: THOR-707 in combination with a checkpoint inhibitor, Q3W
Dose Escalation: THOR-707 will be administered in sequential ascending doses in combination with a checkpoint inhibitor via IV administration Q3W until unacceptable toxicity, disease progression, or withdrawal of consent.
Drug: THOR-707
THOR-707 will be administered as specified under Arm description.

Drug: Checkpoint inhibitor
Checkpoint inhibitor will be administered as specified under Arm description.




Primary Outcome Measures :
  1. Rate of Dose-Limiting Toxicities (DLTs) [ Time Frame: Study Day 1 up to Day 29 ]
    Based on toxicities observed

  2. Maximum Tolerated Dose (MTD) [ Time Frame: Study Day 1 up to Day 29 ]
    Based on toxicities observed

  3. Recommended Phase 2 Dose [ Time Frame: Study Day 1 up to Day 29 ]
    Based on toxicities observed


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) according to RECIST version 1.1 [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on Investigator review of radiographic imaging.

  2. Duration of Response (DOR) according to RECIST version 1.1 [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on Investigator review of radiographic imaging.

  3. Progression-Free Survival (PFS) according to RECIST version 1.1 [ Time Frame: Study Day 1 until the date of first documented progression or date of death from any cause, assessed up to 24 months ]
    Based on Investigator review of radiographic imaging.

  4. Overall Survival according to RECIST version 1.1 [ Time Frame: Study Day 1 up to time of death, assessed up to 24 months ]
    Based on Investigator review of radiographic imaging.

  5. Time to Response (TTR) according to RECIST version 1.1 [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on Investigator review of radiographic imaging.

  6. Disease Control Rate (DCR) according to RECIST version 1.1 [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on Investigator review of radiographic imaging.

  7. Immunophenotyping of peripheral blood at various timepoints [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on appropriate assay.

  8. Immunophenotyping of tumor samples at various timepoints [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on appropriate assay.

  9. Assess presence of antibodies to THOR-707 at various timepoints [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on appropriate assay.

  10. Assess plasma concentration of THOR-707 at various timepoints [ Time Frame: Study Day 1, assessed up to 24 months ]
    Based on appropriate assay.



Information from the National Library of Medicine

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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

Key Inclusion Criteria:

  • Measurable disease per RECIST v1.1.
  • Life expectancy greater than or equal to 12 weeks.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Adequate cardiovascular, hematological, liver, and renal function.
  • Histologically or cytologically confirmed diagnosis of advanced and/or metastatic solid tumors with at least one tumor lesion with location accessible to safely biopsy per clinical judgment of the Investigator.
  • Prior anti-cancer therapy is allowed as long as any treatment related toxicity is resolved to an appropriate level.
  • Females of childbearing potential and men who are not surgically sterile must agree to use medically-accepted method of birth control during the study and for at least 3 months after last dose of treatment.
  • [Females] Negative serum pregnancy test within 7 days prior to initiating study treatment in premenopausal women and women less than 12 months after menopause.
  • [Males] Agreement to refrain from donating or banking sperm during the treatment period and for at least 3 months after last dose of study treatment.

Key Exclusion Criteria:

  • Radiotherapy ≤ 14 days prior to first dose of study drug (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment).
  • Treated with systemic anti-cancer therapy or an investigational agent within 2 weeks prior to start of study drug treatment (within 4 weeks for immunotherapy and tyrosine kinase inhibitor therapy).
  • Major surgery ≤ 30 days prior to first dose of study drug, or has not recovered to at least Grade 1 from adverse effects from such procedure, or anticipation of the need for major surgery during study treatment.
  • Active autoimmune disease requiring systemic treatment within the past 3 months or have a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents.
  • Primary central nervous system (CNS) disease or leptomeningeal disease; known CNS metastases unless treated, are asymptomatic, are without evidence of radiological progression for at least 8 weeks, and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days prior to Screening.
  • Abnormal pulmonary function, including history of pneumonitis, active pneumonitis, interstitial lung disease requiring the use of steroids, idiopathic pulmonary fibrosis, confirmed pleural effusion, severe dyspnea at rest or requiring supplementary oxygen therapy.
  • History of allogenic or solid organ transplant.
  • Known human immunodeficiency virus (HIV) infection or active infection with hepatitis B or C.
  • Clinically significant bleeding within 2 weeks prior to initial THOR-707 dose (e.g., gastrointestinal bleeding, intracranial hemorrhage).
  • Prior diagnosis of deep vein thrombosis or pulmonary embolism within 3 months.
  • Severe or unstable cardiac condition within 6 months prior to starting study treatment, such as congestive heart failure (New York Heart Association Class III or IV), cardiac bypass surgery or coronary artery stent placement, angioplasty, cardiac ejection fraction below the lower limit of normal, unstable angina, medically uncontrolled hypertension (e.g. ≥160 mm Hg systolic or ≥100 mm Hg diastolic), uncontrolled cardiac arrhythmia requiring medication (≥ grade 2, according to NCI CTCAE v5.0), or myocardial infarction.
  • History of non-pharmacologically induced prolonged corrected QT interval determined using Fridericia's formula (QTcF) > 480 milliseconds (msec).
  • Known hypersensitivity to any components of THOR-707, PEG, pegylated drugs, or checkpoint inhibitors for applicable cohorts.
  • Active second malignancy, or history of previous malignancy that would impact the assessment of any study endpoints. Subjects with non-melanomatous skin cancer or cervical cancer that has been curatively surgically resected are eligible.
  • Any serious medical condition (including pre-existing autoimmune disease or inflammatory disorder), laboratory abnormality, psychiatric condition, or any other significant or unstable concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy or would make the subject inappropriate for the study.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 3 months after the last dose of study treatment.
  • Concurrent therapy with any other investigational agent, vaccine, or device. Concomitant participation in observational studies is acceptable after Sponsor approval.

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): NCT04009681


Contacts
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Contact: David Luo 8587504789 ext 8587504789 dluo@synthorx.com

Locations
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Australia
Synthorx Investigational Site Recruiting
Perth, Australia
Sponsors and Collaborators
Synthorx, Inc.
Investigators
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Study Director: Joseph Leveque, M.D. Synthorx, Inc.

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Responsible Party: Synthorx, Inc.
ClinicalTrials.gov Identifier: NCT04009681     History of Changes
Other Study ID Numbers: THOR-707-101
First Posted: July 4, 2019    Key Record Dates
Last Update Posted: July 29, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Synthorx, Inc.:
Synthorx
THOR-707
THOR 707
Interleukin 2
Interleukin-2
IL2
oncology
immuno-oncology
immunotherapy
IL-2

Additional relevant MeSH terms:
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Interleukin-2
Antineoplastic Agents
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs