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

Metastasis Clinical Trial

— HAMMER  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04009681
• Other study ID #: THOR-707-101 (TCD16843)
• Secondary ID: U1111-1298-72812
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 20, 2019
• Est. completion date: June 2026

Study information

• Verified date: April 2024
• Source: Synthorx, Inc, a Sanofi company
• Contact: Trial Transparency email recommended Toll Free Number for US and
• Phone: 800-633-1610
• Email: Contact-US[@]sanofi.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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) in Cohorts A, B, C, D, and G, and adverse events (AEs)/serious adverse event (SAE) profile in Cohorts A, B, C, D, E, F, and G)

• Define the Maximium Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of THOR-707 as a single agent and as a combination therapy (Cohorts A, B, C, D, and G)

• Evaluate preliminary anti-tumor activity of THOR-707 as a single agent by determination of the objective response rate (ORR) defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Cohort H only)

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 (Cohorts A, B, C, D, E, F, and G)

• 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

• Evaluate the safety and tolerability of THOR-707 monotherapy QW/Q2W (AE/serious adverse event [SAE] profile) (Cohort H only).

Description:

The study duration per participant is approximately 24 months (inclusive of follow-up). Cohorts A, B, C, and D have been completed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 250
• Est. completion date: June 2026
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Key Inclusion Criteria:

• Measurable disease per RECIST v1.1. For Cohort G participants must have at least 1 measurable lesion, and for Part 3 (Cohorts E, F and H) participants must have at least 2 measurable lesions to safely perform mandatory pre & on-treatment biopsy.

• Life expectancy greater than or equal to 12 weeks.

• For Part 2 exclusively: While it is highly preferred to enroll subjects who are naïve to PD-1 inhibitors into a Part 2 dose escalation cohort, this is not an enrollment requirement. However, subjects who enroll into a Part 2 safety expansion cohort must be naïve to PD-1 inhibitors. If such subject is unable to meet this requirement but otherwise remains a good candidate for study enrollment, the Investigator should discuss with the Sponsor whether the subject may be enrolled.

• 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.

• Caution: Cohorts E & F enrollment will include only patients with tumors for which anti-PD(L)1 as single agent or in combination treatments are approved.

• Caution: For Cohort H, the participant must have received at least one prior line of therapy for metastatic melanoma and/or does not have any standard of care (SoC) treatment option or participant declines or is intolerant to be treated with SoC treatment.

• Subjects with advanced or metastatic solid tumors who have refused SoC; or for whom no reasonable SoC exists that would confer clinical benefit; or for whom standard therapy is intolerable, not effective, or not accessible.

• 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 least7 days (for Cohorts A, B, G and H), at least 2 months (for Cohort D), or at least 4 months (for Cohorts C, E and F) for females, and for at least 3 days for males [corresponding to the time needed to eliminate study intervention] after the last dose of study intervention.

• [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 days after last dose of study treatment.

• In Spain, Chile, and Argentina: Only cohorts G and H will be open to enrollment.

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).

• Subjects who experienced Grade 3 or higher immune-related toxicity from prior immuno-oncology 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.

• Uncontrolled diabetes mellitus or other uncontrolled immune-related endocrinopathies in the opinion of the Investigator.

• Known human immunodeficiency virus (HIV) infection or active infection with hepatitis C.

• For known uncontrolled hepatitis B virus (HBV) infection:

i. 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. ii. Positive anti-HBc, positive anti HBs, negative HBsAg, and HBV virus load without HBV therapy are eligible.

• Received a live-virus vaccination =14 days prior to first dose of study drug. Seasonal flu and other inactivated vaccines that do not contain live virus are permitted.

• 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 any components of THOR-707, PEG, pegylated drugs, and E. coli derived-protein, 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 for at least 7 days (for Cohorts A, B, G, and H), at least 2 months (for Cohort D), or at least 4 months (for Cohorts C, E, and F) for females and for at least 3 days for males [corresponding to the time needed to eliminate study intervention] after the last dose of study intervention.

• 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.

• For participants in Cohort H: Participants with uveal or ocular or desmoplastic metastatic melanoma.

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

Related Conditions & MeSH terms

• Metastasis
• Neoplasm Metastasis

Intervention

Drug:
• THOR-707
Pharmaceutical form: solution for intravenous (IV) administration; Route of administration: IV administration
• Checkpoint inhibitor
Pharmaceutical form: solution for IV administration; Route of administration: IV administration
• anti-EGFR antibody
Pharmaceutical form: solution for IV administration; Route of administration: IV administration

Locations

Country	Name	City	State
Argentina	Investigational Site Number-7002	Buenos Aires
Australia	Investigational Site Number-2004	New South Whales
Australia	Investigational Site Number-2001	Perth
Australia	Investigational Site Number-2002	Victoria
Australia	Investigational Site Number-2003	Victoria
Chile	Investigational Site Number- 6001	Santiago
Chile	Investigational Site Number-6002	Santiago
Singapore	Investigational Site Number-4002	Singapore
Singapore	Investigational Site-4001	Singapore
Spain	Investigational Site Number-5001	Barcelona
Spain	Investigational Site Number-5006	Barcelona
Spain	Investigational Site Number-5007	Barcelona
Spain	Investigational Site Number-5002	Madrid
Spain	Investigational Site Number-5003	Madrid
Spain	Investigational Site Number-5004	Madrid
Spain	Investigational Site Number-5005	Madrid
Spain	Investigational Site Number-5105	Madrid
United States	Investigational Site Number-1007	Dallas	Texas
United States	Investigational Site Number-1005	Denver	Colorado
United States	Investigational Site Number-1002	Houston	Texas
United States	Investigational Site Number-1003	Nashville	Tennessee
United States	Investigational Site Number-1001	San Antonio	Texas
United States	Investigational Site Number-1004	Sarasota	Florida
United States	Investigational Site Number-1008	Scottsdale	Arizona

Sponsors (1)

Lead Sponsor	Collaborator
Synthorx, Inc, a Sanofi company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Chile,  Singapore,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of Dose-Limiting Toxicities (DLTs)- Cohorts A, B, C, and D	Based on toxicities observed	Study Day 1 up to Day 29
Primary	Maximum Tolerated Dose (MTD)- Cohorts A, B, C, and D	Based on toxicities observed	Study Day 1 up to Day 29
Primary	Recommended Phase 2 Dose (RP2D)- Cohorts A, B, C, and D	Based on toxicities observed	Study Day 1 up to Day 29
Primary	Number of participants with treatment emergent adverse events, serious adverse events, and laboratory abnormalities - Cohorts A, B, C, D, E, F, and G	Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, vital signs, and ECG parameters.	Study Day 1 up to approximately 24 months
Primary	Rate of Dose-Limiting Toxicities (DLTs) -Cohort G	Based on toxicities observed	Study Day 1 up to Day 42 (6 week-cycle)
Primary	Recommended Phase 2 Dose (RP2D) of THOR-707- Cohort G	Based on toxicities observed	Study Day 1 up to Day 42 (6 week-cycle)
Primary	Maximum Tolerated Dose (MTD)- Cohort G	Based on toxicities observed	Study Day 1 up to Day 42 (6 week-cycle)
Primary	Objective Response Rate (ORR) according to RECIST version 1.1 -Cohort H	ORR, 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.	Study Day 1 up to approximately 24 months
Secondary	Objective Response Rate (ORR) according to RECIST version 1.1 Cohort A, B, C, D, E, F, and G)	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.	Study Day 1 up to approximately 24 months
Secondary	Duration of Response (DOR) according to RECIST version 1.1	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.	Study Day 1 up to approximately 24 months
Secondary	Progression-Free Survival (PFS) according to RECIST version 1.1	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.	Study Day 1 until the date of first documented progression or date of death from any cause, assessed up to approximately 24 months
Secondary	Overall Survival according to RECIST version 1.1	Defined as the time from first dose of THOR-707 to the date of death due to any cause.	Study Day 1 up to time of death, assessed up to approximately 24 months
Secondary	Time to Response (TTR) according to RECIST version 1.1	Defined as the time from first dose of THOR-707 to first documentation of objective response (either CR or PR).	Study Day 1 up to approximately 24 months
Secondary	Disease Control Rate (DCR) according to RECIST version 1.1	Defined as the proportion of subjects who have achieved CR, PR, or stable disease (duration of stable disease should be =3 months).	Study Day 1 up to approximately 24 months
Secondary	Percentage of subjects with no disease progression at 6 months post-treatment	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.	Approximately 6 months after the End of Treatment (EOT)
Secondary	Number of participants with treatment emergent adverse events, serious adverse events, laboratory abnormalities -Cohort H	Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, vital signs, and ECG parameters.	Study Day 1 up to approximately 24 months