TH1902 in Patients With Advanced Solid Tumors

Sponsor

Theratechnologies (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04706962

Collaborator

PPD (Industry)

Enrollment

Locations

Arm

23.9

Anticipated Duration (Months)

11.7

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Open label first-in-human study of TH1902 in solid cancer, with 2 sequential parts:

Part 1 (dose escalation): patients with recurrent advanced solid tumors (all comers) that have relapsed or are refractory to standard chemotherapy, surgery, radiation therapy, and for which no known effective therapies exist.

Part 2 (expansion): selected patient populations with recurrent advanced TNBC, HR+ breast cancer, epithelial ovarian cancer, endometrial cancer, cutaneous melanoma, thyroid cancer, SCLC, prostate cancer and other cancers known to express SORT1 that are refractory to standard therapy

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor TNBC - Triple-Negative Breast Cancer Hormone Receptor-positive Breast Cancer Epithelial Ovarian Cancer Endometrial Cancer Cutaneous Melanoma Thyroid Cancer Small-cell Lung Cancer Prostate Cancer	Drug: TH1902	Phase 1

Detailed Description

This first-in-human study is designed as a multi-center, open-label, with 2 sequential parts:

Part 1 (dose escalation): will comprise patients with recurrent advanced solid tumors (all comers) that have relapsed or are refractory to standard chemotherapy, surgery, radiation therapy, and for which no known effective therapies exist.

Part 2 (expansion): will comprise selected patient populations with recurrent advanced TNBC, HR+ breast cancer, epithelial ovarian cancer, endometrial cancer, cutaneous melanoma, thyroid cancer, SCLC, prostate cancer and other cancers known to express SORT1 that are refractory to standard therapy.

The PK profiles of TH1902 and free docetaxel will be evaluated for all patients in Parts 1 and 2. PK samples will be obtained from patients before and after the dose of TH1902 administered at Cycles 1 and 3 and at odd Cycles beyond Cycle 3 in Part 1, and at odd Cycles in Part 2. Part 1 of this study will use a modified rapid dose-escalation design. A starting dose of 30 mg/m2 is proposed based on the available data for TH1902 and the known safety profile of docetaxel. Dose escalation by dose-doubling will be done for the first 2 dose levels, followed by a modified Fibonacci dose escalation scheme (i.e. dose increases of 67%, 50%, 40% and 33%) thereafter for each dose level. Patients in Part 1 will be monitored for 21 days post Day 1 drug administration of each cycle for study drug toxicity. Dose escalation to the next dose level will proceed following satisfactory review of safety data by the Medical Review Committee (MRC) until the maximum tolerated dose (MTD) is reached. If ≥2 patients in a dose escalation cohort experience an emergent dose-limiting toxicity (DLT) by Day 21 of the first treatment cycle, dose escalation will stop, and the prior dose level will be declared as the MTD. Intermediate dose levels may also be explored. The MTD is defined as the highest dose level at which ≤1 of 6 patients in a dose-level cohort develop an emergent DLT. The dose selection for Part 2 of this study will be based on the MTD and other available data. Once the MTD has been determined in Part 1, patients in Part 2 will be treated at the immediate dose level below the MTD, to further assess the safety and tolerability of TH1902 and the preliminary anti-tumor activity of TH1902. The anti-tumor activity will be evaluated for all patients as per the Response Evaluation Criteria in Solid Tumors (RECIST 1.1).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

This first-in-human study is designed as a multi-center, open-label, with 2 sequential parts: Part 1 (dose escalation): will comprise patients with recurrent advanced solid tumors (all comers) that have relapsed or are refractory to standard chemotherapy, surgery, radiation therapy, and for which no known effective therapies exist. Part 2 (expansion): will comprise selected patient populations with recurrent advanced TNBC, HR+ breast cancer, epithelial ovarian cancer, endometrial cancer, cutaneous melanoma, thyroid cancer, SCLC, prostate cancer and other cancers known to express SORT1 that are refractory to standard therapy.This first-in-human study is designed as a multi-center, open-label, with 2 sequential parts:Part 1 (dose escalation): will comprise patients with recurrent advanced solid tumors (all comers) that have relapsed or are refractory to standard chemotherapy, surgery, radiation therapy, and for which no known effective therapies exist. Part 2 (expansion): will comprise selected patient populations with recurrent advanced TNBC, HR+ breast cancer, epithelial ovarian cancer, endometrial cancer, cutaneous melanoma, thyroid cancer, SCLC, prostate cancer and other cancers known to express SORT1 that are refractory to standard therapy.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1, Open-Label, Dose Escalation and Expansion Study of TH1902 in Patients With Advanced Solid Tumors

Actual Study Start Date :

Mar 4, 2021

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TH1902 TH1902 peptide-drug conjugate	Drug: TH1902 Intravenous infusion Other Names: TH1902 peptide-drug conjugate

Arm

Intervention/Treatment

Experimental: TH1902

TH1902 peptide-drug conjugate

Drug: TH1902

Intravenous infusion

Other Names:

TH1902 peptide-drug conjugate

Outcome Measures

Primary Outcome Measures

Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [Through completion, an average of 12 weeks]
Toxicities will be assessed in each patient by tracking the occurrence of graded Adverse Events (AEs). AEs will be graded according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) v5.0.
Maximum tolerated dose (MTD) of TH1902. [Up to 21 days]
The MTD will be defined as the dose level at which no more than one of six patients experiences a dose limiting toxicity (DLT) after 21 days of treatment have occurred, with the next higher dose having at least 2 of 3 or 2 of 6 patients experiencing a DLT.
Recommended Phase 2 Dose (RP2D) of TH1902. [Up to 24 months]
The RP2D will be determined following the determination of the MTD and an overall assessment of safety as determined by the Safety Committee.

Secondary Outcome Measures

Efficacy in patients [6 weeks]
Anti-tumor activity (efficacy) will be assessed in all patients. Determination of the antitumor activity of TH1902 as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Plasma concentration [48 hours]
The plasma concentration will be measured as part of pharmacokinetic (PK) testing.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must meet all the following criteria in order to be eligible to participate in the study:

Are ≥18 years old males or females.
Are capable of understanding and have voluntarily signed the informed consent document and willing to comply with study requirements.
Have histologically or cytologically confirmed diagnosis of metastatic or advancedstage solid tumor that is refractory to standard therapy.
Have measurable disease according to the RECIST 1.1.
Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Have an expected survival of at least 3 months.
Have a negative pregnancy test result confirmed by a serum beta-human chorionic gonadotropin (β-HCG) test (for women of childbearing potential [WOCBP]) performed at Screening and have a negative pregnancy urine test result on Cycle 1, Day 1. This is not applicable to patients who are unable to become pregnant, including those with bilateral oophorectomy, salpingectomy, tubal ligation and/or hysterectomy or postmenopausal or those that have had definitive radiation therapy to the pelvis. WOCBP are considered postmenopausal if 12 months of spontaneous amenorrhea, or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone levels > 40 mIU/mL, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
WOCBP who are sexually active with a non-sterilized male partner (sterilized males should be ≥6 months post vasectomy and have obtained documentation of the absence of sperm in the ejaculate) and male patients whose sexual partners are WOCBP should agree to remain abstinent (refrain from sexual intercourse of any kind) or use 2 effective methods of contraception, including at least 1 method with a failure rate of <1% per year, during the treatment period and for at least 6 months and 3 months for female and male patients, respectively, following the last dose of TH1902. Periodic abstinence (e.g. calendar, symptothermal, and post-ovulation), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.

• Effective contraceptive measures include the following:

Intrauterine device (e.g. IUD) or intrauterine system plus one barrier method.
Oral, intravaginal, or transdermal combined (estrogen and progestogen) hormonal contraceptive associated with the inhibition of ovulation plus one barrier method.
Oral, implantable or injectable progestogen-only hormonal contraceptive associated with the inhibition of ovulation plus one barrier method.
Bilateral tubal occlusion at least 6 weeks before study drug administration.
Sterilization of male partner (at least 6 months prior to screening). For WOCBP in on the study, the vasectomized male partner should be the sole partner for that patient and must have obtained documentation of the absence of sperm in the ejaculate.
True sexual abstinence when this is in line with the preferred and usual lifestyle of the study patient.
Effective barrier methods are: male or female condoms, diaphragms and spermicides.

WOCBP must agree to not donate ova and agree to ongoing pregnancy testing during the course of the study and must agree not to donate ova for at least 6 months following the last dose of TH1902. Male patients must refrain from donating sperm during the course of the study and for at least 3 months following the last dose of TH1902.
Male patients with WOCBP partners must agree to remain abstinent (refrain from sexual intercourse of any kind) or use a condom (latex condom is recommended) during the treatment period and for at least 3 months after the last dose of TH1902 to avoid exposing the embryo, if the vasectomy has been performed less than 6 months or documentation of the absence of sperm in the ejaculate has not been obtained. Periodic abstinence (e.g. calendar, symptothermal, and post-ovulation,), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.
Patients with Human Immunodeficiency Virus (HIV)/Hepatitis B (HBV)/Hepatitis C (HBC) will be allowed to enter into the study provided the following criteria are met:

Patients with HIV infection must have CD4+ T-cell (CD4+) counts ≥ 350 cells/µL.
The following eligibility criteria are for patients with evidence of chronic HBV infection or patients with history of chronic hepatitis C virus (HCV) or who are virologically suppressed on HCV treatment:
Liver-related laboratory eligibility criteria should be the same as that for the general population.
Exceptions: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and bilirubin criteria may be less stringent in patients with cancers such as hepatocellular carcinoma and cholangiocarcinoma in whom hepatic function based on Child-Pugh score should be used.
Patients with chronic HBV infection with active disease who meet the criteria for anti-HBV therapy should be on a suppressive antiviral therapy prior to initiation of cancer therapy. o Patients on concurrent HCV treatments must have HCV below the limit of quantification.
Patients with untreated HCV may be enrolled if the HCV is stable, the patient is not at risk for hepatic decompensation, and the investigational cancer treatment is not expected to exacerbate the HCV infection.

Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry (except for stable sensory neuropathy ≤ Grade 2 and alopecia).

Patients must meet the following additional criterion to enter Part 2 of the study:

Histologically or cytologically confirmed TNBC, HR+ breast cancer, epithelial ovarian cancer, endometrial cancer, cutaneous melanoma, thyroid cancer, SCLC, prostate cancer or other cancer known to express SORT1 that is refractory to standard therapy.

Exclusion Criteria:

Patients who meet any one of the following criteria at baseline will be excluded from study participation:

Have received chemotherapy, biologic therapy, immunotherapy, radiotherapy (except palliative radiation delivered to <20% of bone marrow), or investigational agents within 4 weeks before the first dose of study drug. Patients who have received targeted therapy (investigational or approved) will not have received their last dose within 4 weeks, or within 5 half-lives (whichever is shorter).
Have known hypersensitivity to taxanes, including docetaxel, or to any excipients in TH1902 study drug (e.g. polysorbate-80, predominantly known as Tween® 80).
Have experienced severe toxicity with previous taxane treatment.
Patients with leptomeningeal disease or spinal cord compression or active brain metastases are ineligible for enrollment. Patients with treated brain metastasis that are stable for 4 weeks or longer, and not requiring steroids, are eligible for treatment. Patients with history of brain metastasis should have a magnetic resonance imaging (MRI) within 4 weeks of initiating treatment. For patients where MRI is contraindicated (e.g. due to tissue expanders), brain computerized tomography (CT) may be obtained after discussion with Sponsor.
Pregnant, breastfeeding, or planning to become pregnant during the treatment period.
Had any acute viral (including COVID-19), bacterial, or fungal infection that requires parenteral therapy within 14 days prior to study treatment (Cycle 1, Day 1).
Have received a live vaccine within 30 days prior to administration of the study drug.
Had treatment with cytochrome P450 CYP3A4 or CYP3A5 enzyme-inducing or enzyme inhibiting drugs within 14 days prior to treatment with study drug (Cycle 1, Day 1).
Have any of the following hematologic abnormalities at baseline:

Hemoglobin < 9 g/dL (90 g/L). Patients may be transfused with packed red blood cells (within the 21-day screening period) prior to TH1902 infusion, if clinically warranted. A post-transfusion hemoglobin assessment may qualify the patient for participation.
Absolute neutrophil count < 1.5 x 109/L (1500/mm3)
Platelet count < 100 x 109/L (100,000/mm3)

Have any of the following serum chemistry abnormalities at baseline:

Bilirubin > upper limit of normal (ULN).
AST and/or ALT > 1.5 times the upper limit of reference range (ULRR), or >5 times ULRR for patients with documented liver metastases.
Serum creatinine > 1.5 times ULN and/or creatinine clearance (CrCl) < 50 mL/min (calculated according to the Cockcroft and Gault formula):
Female CrCl = (140 - age in years) × weight in kg × 0.85 / (serum creatinine in mg/dL x 72)
Male CrCL = (140 - age in years) × weight in kg × 1.00 / (serum creatinine in mg/dL x 72)

Baseline corrected interval between Q and T waves on electrocardiogram (ECG) (QTc) ≥ 470 msec using Fridericia's formula. 12. Have unstable or uncompensated respiratory, cardiac, hepatic or renal disease or any other organ system dysfunction, medical condition, or laboratory abnormality which, in the opinion of the investigator, would either compromise the patient's safety or interfere with the evaluation of the study drug safety and anti-tumor activity.
Have evidence of persistent Grade 2 or greater neurotoxicity. 14. Have any of the following ocular conditions at baseline:

Active or chronic corneal disorder, including but not limited to Sjogren's, Fuch's corneal dystrophy, history of corneal transplantation, active herpetic keratitis, as well as other active ocular conditions requiring ongoing therapy.
Any clinically significant corneal disease that prevents adequate monitoring of drug induced keratopathy.
Laser in-situ keratomileusis (LASIK) procedure performed within 1 year or less.
Cataract surgery within 3 months or less.
Patients will not be allowed to use contacts unless advised by an eye care provider for adverse event treatment during the study treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai	Los Angeles	California	United States	90048
2	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
3	START Midwest	Grand Rapids	Michigan	United States	49546
4	Gettysburg Cancer Center	Gettysburg	Pennsylvania	United States	17325
5	Mary Crowley Cancer Research	Dallas	Texas	United States	75230
6	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030