IRB Study Number 23-421
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective:
To characterize the safety, tolerability, and DLT and to determine the MTD and the RP2D of TORL-1-23 administered as monotherapy in participants with advanced cancer
Secondary Objectives:
To characterize the PK of TORL-1-23 and its breakdown products (MMAE and TORL-1-23-MAB
To assess the preliminary antitumor activity of TORL-1-23 in participants with advanced cancer
To assess the immunogenicity of TORL-1-23
Inclusion Criteria
Female or male ≥18 years of age willing and able to provide informed consent
Disease Type:
For Part 1:
• Histologically or cytologically confirmed diagnosis of advanced (unresectable) or metastatic solid tumor malignancy that is not responsive to accepted standard therapies or for which there is no standard therapy
For Part 2 Cohort 2A:
• Histologically or cytologically confirmed diagnosis of advanced (unresectable) or metastatic ovarian, primary peritoneal, or fallopian tube cancer
• Patient’s tumor must be positive for claudin 6 expression as defined by the claudin 6 reference laboratory assay (Section 6.3). If the testing was not previously completed through the Sponsor’s designated central laboratory, tumor tissue will be required for submission for CLDN6 testing prior to C1D1.
• Patients must have platinum-resistant disease, defined as the following:
If participants received only 1 line of platinum-based therapy, they must have completed 4 or more cycles of platinum-containing therapy, must have achieved a CR or PR, and progressed >3 months but ≤6 months after the last dose of platinum.
Participants who have received more than 1 line of platinum-based therapy must have progressed on or within 6 months after the last dose of platinum.
Note: This should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression (per RECIST 1.1). Patients who are platinum-refractory during front-line treatment are excluded (Section 4.2)
• Patients must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, and for whom single-agent therapy is appropriate as the next line of treatment:
a. Adjuvant ± neoadjuvant considered one line of therapy
b. Maintenance therapy (eg, bevacizumab, PARP inhibitors) will be considered as part of the preceding line of therapy (ie, not counted independently)
c. Therapy changed due to toxicity in the absence of progression will be considered as part of the same line (ie, not counted independently)
d. Hormonal therapy will not be counted as a separate line of therapy.
For Part 2 Cohort 2B:
• Histologically or cytologically confirmed diagnosis of advanced (unresectable) or metastatic solid tumor malignancy that is not responsive to accepted standard therapies or for which there is no standard therapy
• Patient’s tumor must be positive for claudin 6 expression as defined by the claudin 6 reference laboratory assay (Section 6.3). If the testing was not previously completed through the Sponsor’s designated central laboratory, tumor tissue will be required for submission for CLDN6 testing prior to C1D1.
• Note: patients with ovarian cancer who have received 4 lines or more prior systemic anticancer therapy could be eligible.
For Part 2 Cohort 2C:
• Histologically confirmed diagnosis of advanced (unresectable) or metastatic NSCLC that has documented radiographical progression (per RECIST 1.1) during or following their last systemic anti-cancer therapy.
• progressed on or following treatment and for which no alternative standard therapy exists and those who are not indicated for a checkpoint inhibitor, platinum-based therapy, epidermal growth factor receptor (EGFR) TKI, BRAF V600E mutation, ALK or ROS-targeted therapy, or KRAS inhibitors. Participants who have progressed after prior such therapies and have exhausted all available standard of therapy (eg, platinum-based chemotherapy for participants without oncogenic drivers after a checkpoint inhibitor) may be eligible.
• Patient’s tumor must be positive for claudin 6 expression as defined by the claudin 6 reference laboratory assay (Section 6.3). If the testing was not previously completed through the Sponsor’s designated central laboratory, tumor tissue will be required for submission for CLDN6 testing prior to C1D1.
For Part 2 Cohort 2D (excluding South Korea):
• Histologically or cytologically confirmed diagnosis of advanced (unresectable) or metastatic solid tumor malignancy that is not responsive to accepted standard therapies or for which there is no standard therapy
• Patient’s tumor must be claudin 6 negative/low as defined by the claudin 6 reference laboratory assay (Section 6.3). If the testing was not previously completed through the Sponsor’s designated central laboratory, tumor tissue will be required for submission for CLDN6 testing prior to C1D1.
For Part 2 Cohort 2E (TORL-1-23 combination with bevacizumab)
• Relapsed and/or progressive disease (PD) on last treatment regimen and one of the following:
Platinum resistant (see definition in 2A) and received no more than 4 prior lines of therapy (see definition of lines of therapy in 2A) and received no more than 1 additional line of therapy after becoming platinum resistant
Platinum sensitive (response duration of 6 months or longer from last dose of platinum therapy) and the following:
Received at least 2 platinum-based therapies OR
1 platinum and 1 non-platinum-based therapy (if unable to receive a second platinum regimen due to toxicity) or received at least 1 platinum-based therapy (if the regimen contained a PARP inhibitor given as maintenance treatment)
Measurable disease, per RECIST v1.1
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Able to tolerate intravenous blood sampling for PK, has no known intolerance or hypersensitivity to IMP or excipients, and able to comply with study requirements
Adequate organ function, based on the following laboratory values: (See protocol)
Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours before starting study drug treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the participant to be eligible, and participants must agree to use a highly effective birth control method, from the time of the first study drug treatment through 7 months after the last study drug treatment (TORL-1-23 or bevacizumab), or be of nonchildbearing potential. Highly effective is defined as combined (estrogen and progestogen containing) hormonal contraception (eg, oral, intravaginal, transdermal), progestin-only hormonal contraception associated with inhibition of ovulation (eg, oral, injectable, implantable, intrauterine device [IUD], intrauterine hormone-releasing system [IUS]), bilateral tubal occlusion, vasectomized partner, or sexual abstinence. Abstinence refers to ‘true abstinence,’ which means it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptotherma, post-ovulation methods), declaration of abstinence for the duration of exposure to study treatment, and withdrawal are not acceptable methods of contraception. Nonchildbearing potential is defined as follows:
a. ≥45 years of age and has not had menses for >1 year
b. Participants who have been amenorrhoeic for <2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone (FSH) value in the postmenopausal range upon screening evaluation
c. Post-hysterectomy, post-bilateral oophorectomy, or post-tube ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
Female and male participants must agree not to donate eggs or sperm, respectively, from the first study-drug treatment through 90 days after the last dose of TORL-1-23 or 6 months after the last dose of bevacizumab.
Female participants must agree to not breastfeed from the first dose of study treatment through 90 days after the last dose of TORL-1-23 or 6 months after the last dose of bevacizumab.
Male participants must use a condom when having sex with a pregnant woman and when having sex with a woman of childbearing potential from the time of the first study-drug treatment through 4 months after the last study drug treatment. Withdrawal (coitus interruptus) and/or use of a spermicide without a condom are not acceptable methods of contraception or fetal protection. Effective contraception should be considered for a nonpregnant female partner of childbearing potential. Male participants are advised to have semen samples frozen before initiation of TORL-1-23 administration given the potential risk to male fertility.
Exclusion Criteria
Has not recovered [recovery is defined as NCI CTCAE, version 5.0, Grade ≤1] from the acute toxicities of previous therapy, except treatment-related alopecia or laboratory abnormalities otherwise meeting eligibility requirements
For Cohort 2:
a. Cohort 2A
i. Patients with low-grade, borderline ovarian tumors or non-epithelial ovarian cancers
ii. Patients with primary platinum-refractory ovarian, primary peritoneal or fallopian tube cancer, defined as disease that did not respond to or has progressed within 3 months of the last dose of first line platinumcontaining chemotherapy
b. For Cohort 2E:
i. Any prior toxicity that required permanent discontinuation of bevacizumab or other contraindications to receive bevacizumab per institutional guidelines or prescribing information (e.g. recto-sigmoid involvement).
ii. Hemoptysis within 3 months of initiation of study treatment
iii. Nephrotic syndrome within 3 months of initiation of study treatment. If subjects have proteinuria at screening per urine dipstick test ≥2+, participants must have a 24-hour urine collection and testing for protein. Participants are excluded for ≥2 grams of protein per 24 hours.
iv. Bleeding requiring transfusion within 3 months of initiation of study treatment.
v. Current signs/symptoms of bowel obstruction or within three months of initiating study treatment.
vi. Bowel obstruction within 3 months of initiation of study treatment.
vii. History of gastrointestinal perforation. Participants with a history of abdominal fistula will be considered eligible if all of the following are true:
The fistula was surgically repaired or has healed
There has been no evidence of fistula for at least 6 months
There is a low risk of recurrence.
Received prior chemotherapeutic, investigational, radiotherapy, or other therapies for the treatment of cancer within 14 days with small molecule and within 28 days with biologic before the first dose of TORL-1-23. There is no waiting period required for stereotactic radiosurgery (SRS).
Progressive or symptomatic brain metastases. Brain metastases that have been radiated, are asymptomatic, and on a stable or decreasing dose of steroids are allowed. Leptomeningeal disease is excluded.
Grade 2 or greater peripheral neuropathy
Participants must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
History of significant cardiac disease:
• Congestive heart failure >New York Heart Association (NYHA) class 2 within last year
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
• Myocardial infarction less than 6 months before start of study drug
• Anti-arrhythmic therapy (beta blockers are permitted)
• Any unstable ischemic disease or untreated arrhythmia
Known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)
History of another cancer within 3 years before Day 1 of study treatment, with the exception of basal or squamous cell carcinoma of the skin that has been definitively treated. Participants with malignancies with a low risk of recurrence, including appropriately treated ductal carcinoma in situ (DCIS) of the breast and prostate cancer with a Gleason score less than or equal to 6, are not excluded.
Uncontrolled infection; active, clinically serious infections (CTCAE Grade >2)
Participants with seizure disorder requiring medication
Participants must not be pregnant or breastfeeding
Known hypersensitivity or intolerance to any of the study drugs, study drug classes, or excipients in the formulation
History of having an allogeneic bone marrow or organ transplant
Any condition (concurrent disease, infection, or comorbidity) that interferes with ability to participate in the study, causes undue risk, or complicates the interpretation of safety data, in the opinion of the Investigator.
Participants who are taking any drugs that are strong inducers and/or strong inhibitors of CYP3A4 enzymes
Participants who are taking any drugs that are inhibitors of P-gp
