None listed
Conditions
Brief summary
The primary purpose of this trial is to evaluate the safety and tolerability of A-337, the rate that the drug is processed by the body, and the best dose for treatment in patients with solid tumours. Who is it for? You may be eligible to enroll in this trial if you are aged 18 or over and have been diagnosed with advanced malignant solid tumor known to express EpCAM, that does not respond to standard therapy or for which no standard therapy is available. Study details All participants enrolled in this trial will receive eight doses of A-337, delivered twice per week over four weeks. The dose received by each participant depends on the time of their enrolment and the safety of previous doses. A-337 is an antibody designed to target a specific cancer marker, found in some cancers. Researchers will assess patients for side effects of the medication, and take blood samples until 6 weeks after the first dose. It is hoped that the findings from this trial will determined the optimal dose of A-337 to administer for treatment, and to determine whether A-337 is safe and well tolerated by cancer patients.
Interventions
The conventional 3+3 design (3 patients per dose cohort, with the potential to add 3
additional patients to the same cohort to further evaluate toxicity) will be applied
for dose escalation and MTD determination.
A DLT is defined as a toxicity according to Section 7.1.1 (d) that occurs during the DLT
assessment window (Cycle 1, 4-week treatment period plus 2-week rest period) and
determined by the investigator or by the Sponsor to have a reasonable possibility of
being related to A-337.
Maximum
The conventional 3+3 design (3 patients per dose cohort, with the potential to add 3 additional patients to the same cohort to further evaluate toxicity) will be applied for dose escalation and MTD determination. A DLT is defined as a toxicity according to Section 7.1.1 (d) that occurs during the DLT assessment window (Cycle 1, 4-week treatment period plus 2-week rest period) and determined by the investigator or by the Sponsor to have a reasonable possibility of being related to A-337. Maximum tolerated dose (MTD) is defined as the maximum dose at which no more than one of six evaluable patients in a single cohort experiences a DLT in the first cycle (Cycle 1, 4-week treatment period plus 2-week rest period). This trial will evaluate six adaptive dose levels: 0.15, 0.3, 0.6, 1.2, 2.4 and 3.6 µg/kg. For Cohort 1, patients will receive a dose of 0.15 µg/kg of A-337 twice (on day 1 and day 4) via IV infusion at 6-hour constant rate during the first week, followed by 3 weeks’ treatment with A-337 at 0.15 µg/kg with 6-hour IV infusions twice weekly. For all subsequent cohorts, patients will receive a conditioning dose of 0.3 µg/kg of A-337 twice (on day 1 and day 4) via IV infusion at 6-hour constant rate during the first week, followed by 3 weeks’ treatment with A-337 at one of the following dose levels (0.3, 0.6, 1.2, 2.4 and 3.6 µg/kg) with 6-hour IV infusions twice weekly. Dexamethasone at a dose of 20 mg will be given 1 hour prior to the first conditioning dose of A-337 and the first rampup dose (0.15 µg/kg to 3.6 µg/kg). Administration of Dexamethasone on subsequent doses is given at either 20 mg or 10 mg based on clinical judgement regarding the potential toxicity of A-337. After completion of the dose escalation, up to 12 patients may be enrolled in cohorts at dose levels up to the MTD to obtain additional information on the safety, PK, and PD of monotherapy A-337. Dexamethasone can be administered as either oral or intravenous infusion at the discretion of the investigator. 3+3 Rules for Dose Escalation: A minimum of 3 patients will be enrolled and observed for toxicity in each dose cohort. If the 3 patients initially enrolled in a dose cohort complete the DLT assessment window (Cycle 1, 4-week treatment period plus 2-week rest) without experiencing a DLT, 3 patients will be enrolled at the next higher dose level. There will be a minimum for 72 hours between patients being dosed in each cohort. If 1 of the initial 3 patients enrolled at any dose level experiences a DLT during the DLT assessment window, additional patients will be enrolled at that dose level for a minimum of 6 evaluable for DLT. If a DLT is observed in 1 of the 6 evaluable patients at this dose level, dose escalation will proceed to the next pre-defined dose level. If DLTs are observed in 2 or more of the 6 evaluable patients at a given dose level, the dose escalation will be halted. If this dose level is > or equal to 50% higher than the previous dose level, an intermediate dose level may be evaluated for toxicity in the same manner as described above. If the dose level is < 50% higher than the previous dose level, additional patients will be enrolled at the previous dose level, if necessary, to provide a minimum of 6 evaluable patients. Dose escalation beyond 3.6 µg/kg will be determined jointly by investigators and sponsor based on the clinical safety, pharmacokinetic, and preliminary efficacy data. There will be a minimum for 72 hours between patients being dosed in each cohort. Each treatment cycle will be composed of a 4-week treatment period (the first week with the conditioning doses of 0.15 µg/kg (Cohort 1) 0.3 µg/kg (Cohorts 2-6) on Day 1 and Day 4, 3 weeks with the ramp-up doses from 0.15 to 3.6 µg/kg on Day 1 and Day 4), and followed by 2-week rest. Dose escalation and entry of the next cohort will occur only after acceptable tolerance has been demonstrated throughout the entire Cycle1.
Sponsors
INC Research Pty Ltd
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically confirmed advanced malignant solid tumor that is refractory to, intolerant of, or for which no standard of therapy is available. 2. Advanced solid tumors that are known to widely express EpCAM, including but not limited to colorectal cancer, gastric cancer, lung cancer, ovarian cancer and prostate cancer. 3. At least one measurable tumor lesion as per RECIST criteria v1.1 defined as having at least one dimension with a minimum size of 10 mm in the longest diameter by CT or MRI scan for non-nodal lesions or > or equal to 15 mm in short axis for nodal lesions. Radiographic disease assessment at baseline can be performed up to 28 days prior to the first dose. 4. Adequate archival tumor tissue available or willingness to have a fresh biopsy. A fresh pre-treatment biopsy is compulsory for the first six patients enrolled at the expansion stage. 5. Age > or equal to 18 years 6. ECOG performance status < or equal to 2 7. Life expectancy of at least 3 months 8. Ability to understand the patient information and informed consent form. 9. Signed and dated written informed consent
Exclusion criteria
1. Inadequate hematologic function, defined by: Neutrophil count < 1,500/mm3 (= 1.5 x 10^9/L), Platelet count < 100,000/mm3 (= 100 x 10^9/L), White blood cells (WBC) < 1,500/mm3 (3 x10^9/L), Hemoglobin < 9.0 g/dL at Screening. 2. Abnormal renal or hepatic function as defined by: • ALT and AST > 2 x ULN, in case of liver metastases 3 x ULN • Total bilirubin > 1.5 x ULN • Creatinine clearance < 50 ml/min calculated by the Cockroft-Gault formula or modification of diet in renal disease (MDRD) • Coagulation: International Normalized Ratio (INR) < or equal to 1.6 (unless receiving anticoagulation therapy). Subjects on full-dose oral anticoagulation must be on a stable dose (minimum duration 14 days). If receiving warfarin, the subject must have an INR < or equal to 3.0 and no active bleeding (ie, no bleeding within 14 days prior to first dose of study drug). Subjects on low molecular weight heparin will be allowed. 3. Decompensated liver cirrhosis. 4. Subject with known central nervous system (CNS) metastases, unless metastases are treated and stable for at least 4 weeks and the subject has not been taking systemic steroids < or equal to 10mg prednisone/day or equivalent. Patients with leptomeningeal disease or cord compression are excluded. 5. Any concurrent disease, medical or social condition that could affect compliance with the protocol or interpretation of results as judged by the investigator. In particular, patients with the following conditions are not allowed to enter the study: • Active infection or known bacteremia • Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus or hepatitis C virus • Severe dyspnea or pulmonary dysfunction or need for continuous supportive oxygen inhalation • Insufficient cardiac function defined as NYHA (New York Heart Association) Grade 3 or 4. • History of myocardial infarction or unstable angina within 6 months prior to Day 1. • History of stroke or transient ischemic attack within 6 months prior to Day 1 • Clinically significant cardiac arrhythmias, uncontrolled hypertension SBP>180 mmHg and DBP>100 mmHg • History of autoimmune disease including, not limited to celiac disease, diabetes mellitus type 1, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. 6. Treatment with immune modulators including, but not limited to, cyclosporine and tacrolimus within 2 weeks prior to enrollment; systemic steroids < or equal to 10 mg prednisone or equivalent per day are allowed as well as ophthalmic, inhaled or nasal steroids.. 7. Pregnant, nursing women or women of childbearing potential who are not willing to use effective forms of contraception during participation in the study and at least three months thereafter. Positive pregnancy test (HCG) within 3 days prior to Day 1. 8. Male patients with partners of child-bearing potential who are not willing to use effective contraception during the trial and for at least three months thereafter, unless surgically sterile. 9. Any anti-cancer therapy, including chemotherapy, hormonal therapy, biologic therapy, or radiotherapy within 4 weeks prior to initiation of study treatment with the following exceptions: • Hormonal therapy with gonadotropin-releasing hormone (GnRH) agonists for prostate cancer • Hormone-replacement therapy or oral contraceptives • Palliative radiation to bone metastases > 2 weeks prior to Day 1 10. Patients with previous immunotherapy that has same mechanism of action of A-337 (CD3 activating bi-specific antibody). Patients treated with previous immune checkpoint inhibitors are allowed. 11. Adverse events from prior anti-cancer therapy that have not resolved to Grade < or equal to 1, except for alopecia. 12. Inability to comply with study and follow-up procedures 13. Any other diseases, metabolic dysfunction, physical examination finding or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications
Outcome results
None listed