Clinical trial NCT04009681: A Study Evaluating Safety and Therapeutic Activity of THOR-707 in Adult Subjects With Advanced or Metastatic Solid Tumors (THOR-707-101)
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastasis
Keywords: Synthorx
THOR-707
THOR 707
Interleukin 2
Interleukin-2
IL2
oncology
immuno-oncology
immunotherapy
IL-2
SAR444245
Sanofi
Lead sponsor: Synthorx, Inc, a Sanofi company
Sponsor class: INDUSTRY
First posted: 2019-07-05
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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) 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), disease control rate (DCR), and clinical benefit rate (CBR) 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).

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

Eligibility criteria: 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.

Primary outcomes:
measure: Rate of Dose-Limiting Toxicities (DLTs)- Cohorts A, B, C, and D
timeFrame: Study Day 1 up to Day 29
measure: Maximum Tolerated Dose (MTD)- Cohorts A, B, C, and D
timeFrame: Study Day 1 up to Day 29
measure: Recommended Phase 2 Dose (RP2D)- Cohorts A, B, C, and D
timeFrame: Study Day 1 up to Day 29
measure: Number of participants with treatment emergent adverse events, serious adverse events, and laboratory abnormalities - Cohorts A, B, C, D, E, F, and G
timeFrame: Study Day 1 up to approximately 24 months
measure: Rate of Dose-Limiting Toxicities (DLTs) -Cohort G
timeFrame: Study Day 1 up to Day 42 (6 week-cycle)
measure: Recommended Phase 2 Dose (RP2D) of THOR-707- Cohort G
timeFrame: Study Day 1 up to Day 42 (6 week-cycle)
measure: Maximum Tolerated Dose (MTD)- Cohort G
timeFrame: Study Day 1 up to Day 42 (6 week-cycle)
measure: Objective Response Rate (ORR) according to RECIST version 1.1 -Cohort H
timeFrame: Study Day 1 up to approximately 24 months
Secondary outcomes:
measure: Objective Response Rate (ORR) according to RECIST version 1.1 Cohort A, B, C, D, E, F, and G)
timeFrame: Study Day 1 up to approximately 24 months
measure: Duration of Response (DOR) according to RECIST version 1.1
timeFrame: Study Day 1 up to approximately 24 months
measure: Progression-Free Survival (PFS) according to RECIST version 1.1
timeFrame: Study Day 1 until the date of first documented progression or date of death from any cause, assessed up to approximately 24 months
measure: Overall Survival according to RECIST version 1.1
timeFrame: Study Day 1 up to time of death, assessed up to approximately 24 months
measure: Time to Response (TTR) according to RECIST version 1.1
timeFrame: Study Day 1 up to approximately 24 months
measure: Disease Control Rate (DCR) according to RECIST version 1.1
timeFrame: Study Day 1 up to approximately 24 months
measure: Clinical Benefit Rate (CBR)
timeFrame: Study Day 1 up to approximately 24 months
measure: Number of participants with treatment emergent adverse events, serious adverse events, laboratory abnormalities -Cohort H
timeFrame: Study Day 1 up to approximately 24 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Investigational Site Number-1008
state: Arizona
city: Denver
country: United States
facility: Investigational Site Number-1005
state: Colorado
city: Sarasota
country: United States
facility: Investigational Site Number-1004
state: Florida
city: Nashville
country: United States
facility: Investigational Site Number-1003
state: Tennessee
city: Dallas
country: United States
facility: Investigational Site Number-1007
state: Texas
city: Houston
country: United States
facility: Investigational Site Number-1002
state: Texas
city: San Antonio
country: United States
facility: Investigational Site Number-1001
state: Texas
city: Buenos Aires
country: Argentina
facility: Investigational Site Number-7002
city: New South Whales
country: Australia
facility: Investigational Site Number-2004
city: Perth
country: Australia
facility: Investigational Site Number-2001
city: Victoria
country: Australia
facility: Investigational Site Number-2002
city: Victoria
country: Australia
facility: Investigational Site Number-2003
city: Santiago
country: Chile
facility: Investigational Site Number- 6001
city: Santiago
country: Chile
facility: Investigational Site Number-6002
city: Singapore
country: Singapore
facility: Investigational Site Number-4002
city: Singapore
country: Singapore
facility: Investigational Site-4001
city: Barcelona
country: Spain
facility: Investigational Site Number-5001
city: Barcelona
country: Spain
facility: Investigational Site Number-5006
city: Barcelona
country: Spain
facility: Investigational Site Number-5007
city: Madrid
country: Spain
facility: Investigational Site Number-5002
city: Madrid
country: Spain
facility: Investigational Site Number-5003
city: Madrid
country: Spain
facility: Investigational Site Number-5004
city: Madrid
country: Spain
facility: Investigational Site Number-5005
city: Madrid
country: Spain
facility: Investigational Site Number-5105
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: