Resumen

Objetivos primarios: * Evaluar la seguridad y tolerabilidad de THOR-707 como agente único y como terapia combinada (identificar toxicidades limitantes de dosis [DLT] en las Cohortes A, B, C, D y G, y el perfil de eventos adversos [EA]/eventos adversos graves [EAG] en las Cohortes A, B, C, D, E, F y G) * Definir la dosis máxima tolerada (DMT) y/o la dosis recomendada de fase 2 (RP2D) de THOR-707 como agente único y como terapia combinada (Cohortes A, B, C, D y G) * Evaluar la actividad antitumoral preliminar de THOR-707 como agente único mediante la determinación de la tasa de respuesta objetiva (TRO) definida según los Criterios de Evaluación de Respuesta en Tumores Sólidos (RECIST) Versión 1.1 (solo Cohorte H) Objetivos secundarios: * Evaluar la actividad antitumoral preliminar de THOR-707 como agente único y como terapia combinada mediante la determinación de la tasa de respuesta objetiva (TRO) definida según los Criterios de Evaluación de Respuesta en Tumores Sólidos (RECIST) Versión 1.1 (Cohortes A, B, C, D, E, F y G) * Determinar el tiempo hasta la respuesta (TTR), la duración de la respuesta (DOR), la supervivencia libre de progresión (SLP), la supervivencia global (SG), la tasa de control de la enfermedad (TCE) y la tasa de beneficio clínico (TBC) de THOR-707 como agente único y como terapia combinada * Evaluar la seguridad y tolerabilidad de la monoterapia con THOR-707 semanal/quincenal (perfil de EA/EAG) (solo Cohorte H).

Descripción detallada

La duración del estudio por participante es de aproximadamente 24 meses (incluyendo el seguimiento). Las Cohortes A, B, C y D han sido completadas.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

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.

Criterios de exclusión

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.

Intervenciones

drug

THOR-707

Pharmaceutical form: solution for intravenous (IV) administration; Route of administration: IV administration

drug

Checkpoint inhibitor

Pharmaceutical form: solution for IV administration; Route of administration: IV administration

drug

anti-EGFR antibody

Pharmaceutical form: solution for IV administration; Route of administration: IV administration

Estudio abierto, multicéntrico de fase 1/2 de escalada de dosis y expansión de THOR-707 como agente único y como terapia combinada en sujetos adultos con tumores sólidos avanzados o metastásicos

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

THOR-707

Checkpoint inhibitor

anti-EGFR antibody

Ubicaciones

Investigational Site Number-7002

Patrocinadores