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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Synthorx Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 May 2023 → 2 Dec 2025

Decision date (initial)

2024-02-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Synthorx Inc.

External identifiers

EU CT number

2023-508422-95-00

EudraCT number

2022-003500-33

WHO UTN

U1111-1298-7281

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Pharmacodynamic, Pharmacokinetic, Safety, Therapy

• 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 3

1. 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)
2. 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
3. Evaluate the safety and tolerability of THOR-707 monotherapy QW/Q2W (AE/serious adverse event [SAE] profile) (Cohort H only)

Conditions and MedDRA coding

Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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
2. Life expectancy greater than or equal to 12 weeks
3. 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
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Adequate cardiovascular, hematological, liver, and renal function
6. 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.
7. 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
8. Prior anti-cancer therapy is allowed as long as any treatment related toxicity is resolved to an appropriate level
9. 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 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
10. [Females] Negative serum pregnancy test within 7 days prior to initiating study treatment in premenopausal women and women less than 12 months after menopause
11. [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
12. In Spain, Chile, and Argentina: Only cohorts G and H will be open to enrollment

Exclusion criteria 25

1. Radiotherapy ≤ 14 days prior to first dose of study drug (palliative radiation or stereotactic radiosurgery within 7 days prior to start of study treatment)
2. 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)
3. Subjects who experienced Grade 3 or higher immune-related toxicity from prior immuno-oncology therapy
4. 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
5. 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
6. 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
7. 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
8. Parenteral antibiotics within 14 days of the first dose of study drug
9. History of allogenic or solid organ transplant
10. Uncontrolled diabetes mellitus or other uncontrolled immune-related endocrinopathies in the opinion of the Investigator
11. Known human immunodeficiency virus (HIV) infection or active infection with hepatitis C
12. 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.
13. 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
14. Clinically significant bleeding within 2 weeks prior to initial THOR-707 dose (e.g., gastrointestinal bleeding, intracranial hemorrhage)
15. Prior diagnosis of deep vein thrombosis or pulmonary embolism within 3 months
16. 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
17. 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
18. 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
19. 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
20. 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
21. 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
22. Concurrent therapy with any other investigational agent, vaccine, or device. Concomitant participation in observational studies is acceptable after Sponsor approval
23. 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
24. Subjects with baseline oxygen saturation <92% are not eligible for enrollment
25. For participants in Cohort H: Participants with uveal or ocular or desmoplastic metastatic melanoma

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Rate of Dose-Limiting Toxicities (DLTs) - Cohorts A, B, C, and D
2. Rate of Dose-Limiting Toxicities (DLTs) -Cohort G
3. Maximum Tolerated Dose (MTD)- Cohorts A, B, C, and D
4. Recommended Phase 2 Dose (RP2D) or THOR-707- Cohorts A, B, C, and D
5. Recommended Phase 2 Dose (RP2D) of THOR-707- Cohort G
6. Maximum Tolerated Dose (MTD)- Cohort G
7. Number of participants with treatment emergent adverse events, serious adverse events, and laboratory abnormalities – Cohorts A, B, C, D, E, F, and G
8. Objective Response Rate (ORR) according to RECIST version 1.1 -Cohort H

Secondary endpoints 8

1. ORR according to RECIST version 1.1 Cohort A, B, C, D, E, F, and G)
2. Duration of Response (DOR) according to RECIST version 1.1
3. Progression-Free Survival (PFS) according to RECIST version 1.1
4. Overall Survival according to RECIST version 1.1
5. Time to Response (TTR) according to RECIST version 1.1
6. Disease Control Rate (DCR) according to RECIST version 1.1
7. Percentage of subjects with no disease progression at 6 months post-treatment
8. Number of participants with treatment emergent adverse events, serious adverse events, laboratory abnormalities -Cohort H

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Synthorx Inc.

Sponsor organisation

Synthorx Inc.

Address

11099 North Torrey Pines Road Suite 190

City

La Jolla

Postcode

92037-1029

Country

United States

Scientific contact point

Organisation

Synthorx Inc.

Contact name

Clinical Sciences and Operations

Public contact point

Organisation

Synthorx Inc.

Contact name

Clinical Sciences and Operations

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications