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

Sponsor

Synthorx, Inc, a Sanofi company (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04009681

Collaborator

(none)

300

Enrollment

Locations

Arms

49.8

Anticipated Duration (Months)

23.1

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objectives:

Evaluate the safety and tolerability of THOR-707 as a single agent and as a combination therapy (identify Dose Limiting Toxcitiy (DLTs), Adverse Events (AEs)/serious adverse event (SAE) profile)
Define the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of THOR-707 as a single agent and as a combination therapy

Secondary Objectives:

Evaluate preliminary anti-tumor activity of THOR-707 as a single agent and as a combination therapy by determination of the objective response rate (ORR) defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Determine time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) of THOR-707 as a single agent and as a combination therapy

Condition or Disease	Intervention/Treatment	Phase
Metastasis	Drug: THOR-707 Drug: Checkpoint inhibitor Drug: anti-EGFR antibody	Phase 1/Phase 2

Detailed Description

The study duration per participant is approximately 24 months (inclusive of follow-up).

Study Design

Study Type:

Interventional

Anticipated 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 as a Combination Therapy in Adult Subjects With Advanced or Metastatic Solid Tumors

Actual Study Start Date :

Jun 20, 2019

Anticipated Primary Completion Date :

Aug 14, 2023

Anticipated Study Completion Date :

Aug 14, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort A-THOR-707 Monotherapy and Dose Escalation 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 Pharmaceutical form: solution for intravenous (IV) administration Route of administration: IV administration Other Names: SAR444245
Experimental: Cohort B-THOR-707 Monotherapy and Dose Escalation 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 Pharmaceutical form: solution for intravenous (IV) administration Route of administration: IV administration Other Names: SAR444245
Experimental: Cohort C-THOR-707 with checkpoint inhibitor and dose escalation Dose Escalation: TTHOR-707 will be administered in sequential ascending doses in combination with a checkpoint inhibitor via IV administration Q3W or every 6 weeks (Q6W) until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: THOR-707 Pharmaceutical form: solution for intravenous (IV) administration Route of administration: IV administration Other Names: SAR444245 Drug: Checkpoint inhibitor Pharmaceutical form: solution for intravenous (IV) administration Route of administration: IV administration
Experimental: Cohort D-THOR-707 with anti-EGFR antibody and dose escalation Dose Escalation: THOR-707 will be administered in sequential ascending doses in combination with an anti-EGFR antibody via IV administration Q3W/QW (once-weekly) (respectively) until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: THOR-707 Pharmaceutical form: solution for intravenous (IV) administration Route of administration: IV administration Other Names: SAR444245 Drug: anti-EGFR antibody Pharmaceutical form: solution for intravenous (IV) administration Route of administration: IV administration

Outcome Measures

Primary Outcome Measures

Rate of Dose-Limiting Toxicities (DLTs) [Study Day 1 up to Day 29]
Based on toxicities observed
Maximum Tolerated Dose (MTD) [Study Day 1 up to Day 29]
Based on toxicities observed
Recommended Phase 2 Dose (RP2D) [Study Day 1 up to Day 29]
Based on toxicities observed

Secondary Outcome Measures

Objective Response Rate (ORR) according to RECIST version 1.1 [Study Day 1, assessed up to 24 months]
Defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR); a confirmed response is a response that persists on repeat-imaging ≥4 weeks after initial documentation of response.
Duration of Response (DOR) according to RECIST version 1.1 [Study Day 1, assessed up to 24 months]
Defined as time from date of first objective response (either CR or PR) to first documentation of radiographic disease progression or death due to any cause, whichever occurs first.
Progression-Free Survival (PFS) according to RECIST version 1.1 [Study Day 1 until the date of first documented progression or date of death from any cause, assessed up to 24 months]
Defined as the time from first dose of THOR-707 to first documentation of radiographic disease progression or death due to any cause, whichever occurs first.
Overall Survival according to RECIST version 1.1 [Study Day 1 up to time of death, assessed up to 24 months]
Defined as the time from first dose of THOR-707 to the date of death due to any cause.
Time to Response (TTR) according to RECIST version 1.1 [Study Day 1, assessed up to 24 months]
Defined as the time from first dose of THOR-707 to first documentation of objective response (either CR or PR).
Disease Control Rate (DCR) according to RECIST version 1.1 [Study Day 1, assessed up to 24 months]
Defined as the proportion of subjects who have achieved CR, PR, or stable disease (duration of stable disease should be ≥3 months).
Percentage of subjects with no disease progression at 6 months post-treatment [6 months after the End of Treatment (EOT)]
The End of Treatment (EOT) visit is performed within 30 days after a subject discontinues from study drug administration and prior to the subject beginning any subsequent anti-cancer therapy.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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. (Caution: Cohort D only patients with KRAS mutant colon cancer have not typically benefitted from the addition of cetuximab in earlier lines of therapy)
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 within the previous 6 months, including 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.
Parenteral antibiotics within 14 days of the first dose of study drug.
History of allogenic or solid organ transplant.
Known human immunodeficiency virus (HIV) infection or active infection with hepatitis

Known uncontrolled hepatitis B virus (HBV) infection:
Anti-HBV therapy started before initiation of IMP and HBV viral load <2000 IU/mL (104 copies/mL) are eligible. The anti-HBV therapy should continue throughout the treatment period
Positive anti-HBc, positive anti HBs, negative HBsAg, and HBV virus load without HBV therapy are eligible
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) > 450 milliseconds (msec) in males or > 470 msec in females.
Known hypersensitivity or contraindications to THOR-707, PEG, pegylated drugs, checkpoint inhibitor, or anti-EGFR antibody 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.
For Cohort D only: patients with symptomatic keratitis and/or symptomatic dry eye should be excluded from enrollment. Patients who wear contact lenses should be advised to avoid contact lenses use as it could result in keratitis.
Subjects with baseline oxygen saturation <92% are not eligible for enrollment.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number-1008	Scottsdale	Arizona	United States	85250
2	Investigational Site Number-1005	Denver	Colorado	United States	80218
3	Investigational Site Number-1004	Sarasota	Florida	United States	34232
4	Investigational Site Number-1003	Nashville	Tennessee	United States	37203
5	Investigational Site Number-1007	Dallas	Texas	United States	75032
6	Investigational Site Number-1002	Houston	Texas	United States	77030
7	Investigational Site Number-1001	San Antonio	Texas	United States	78229
8	Investigational Site Number-2004	New South Whales		Australia
9	Investigational Site Number-2001	Perth		Australia
10	Investigational Site Number-2002	Victoria		Australia
11	Investigational Site Number-2003	Victoria		Australia
12	Investigational Site Number-4002	Singapore		Singapore
13	Investigational Site-4001	Singapore		Singapore