Hematologic Malignancy, Solid Tumor
Conditions
Brief summary
A Phase 1, Open-Label, Dose Escalation, and Cohort Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Clinical Activity of DT2216, an Antiapoptotic Protein Targeted Degradation Compound, in Subjects with Relapsed or Refractory Malignancies
Detailed description
This study is an open-label, first-in-human, dose escalation study in subjects with histologically or cytologically confirmed advanced or metastatic malignancies who are no longer responsive to approved or accepted standard-of-care interventions. The study will consist of a dose escalation phase followed by confirmation of the recommended phase 2 dose (RP2D). Potentially eligible subjects will undergo screening evaluations (up to 28 days prior to study therapy) and those who meet all protocol-defined eligibility criteria will be enrolled into the study. Subjects who fail screening may be re-screened one time following correction or mitigation of the condition that caused the screen failure; there is no time limit on when a subject may be re-screened. Enrolled subjects will receive a single intravenous (IV) infusion of study drug on Days 1 and 4 weekly for at least 4 weeks, with each cycle consisting of 28 days. Treatment duration for an individual subject may continue for a maximum of 1 year, until disease progression, unacceptable toxicity, subject withdrawal, Investigator's decision for a change in treatment strategy for the individual subject, or death. Longer therapy may be considered for individual subjects upon consultation with the Sponsor's Medical Monitor and overall assessment of benefit:risk. Subjects will be followed for safety for 28 days following the administration of the last study treatment.
Interventions
DRUGDT2216
DT2216 will be administered by intravenous infusion
Sponsors
Dialectic Therapeutics, Inc
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Adults aged 18 years or older on the day of signing informed consent. 2. Provide written informed consent for the trial, including willingness to comply with all study related requirements. 3. Histologically or cytologically confirmed solid tumor. Subjects with more than 1 primary malignancy may be considered upon review with the Sponsor's Medical Monitor 4. Evidence of disease progression or inadequate response on the last regimen as assessed by the Investigator. 5. Has exhausted all curative options or has a contraindication to approved therapies or generally recognized standard-of-care measures for the subject's cancer. 6. Presence of measurable disease as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 8. Has adequate organ functions as defined by the following laboratory parameters at baseline (laboratory parameters outside of these ranges that are deemed clinically insignificant should be discussed with the Medical Monitor): (a) Absolute neutrophil count ≥1.5 x 109/L; (b) hemoglobin ≥9 g/dL; (c) platelet count ≥100,000/mm3; (d) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN); (e) total bilirubin ≤ 1.5 x institutional ULN (exception: subjects with known Gilbert's syndrome and total bilirubin ≤3.0 x ULN at screening or anytime during the prior 6 months are eligible); (f) c) adequate renal function defined as calculated creatinine clearance \>60 mL/min using the Cockcroft-Gault Method (Appendix 3); (g) acceptable coagulation parameters including international normalized ratio (INR) \<1.5 and partial thromboplastin time (PTT) ≤ institutional ULN; (h) serum albumin ≥3.0 g/dL. 9. Left ventricular ejection fraction of ≥50% as assessed by echocardiogram or multi-gated acquisition (MUGA) scan. 10. Adequate washout from the following prior to first dose of study therapy: Palliative radiation ≥ 2 weeks; chemotherapy or targeted therapy ≥ 3 weeks or 5 half-lives; biologic therapy ≥ 4 weeks. 11. Resolution to Grade ≤1 by the National Cancer Institute CTCAE, Version 5.0 (NCI-CTCAE v 5.0) of all clinically significant toxic effects of prior therapies. 12. Female subjects: A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: (a) Not a woman of childbearing potential (WOCBP); (b) WOCBP who agrees to follow the contraceptive guidance during the study treatment period and for at least 120 days after the last dose of study treatment. 13. Female subject of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving any dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 14. Male subject is eligible to participate if he agrees to follow the acceptable contraceptive guidance during the study treatment period and for at least 120 days after the last dose of study treatment. \-
Exclusion criteria
Diagnosis and Main Criteria for Inclusion: Subjects are eligible to be included in the study only if all of the following criteria are met: Inclusion Criteria 1. Adults aged 18 years or older on the day of signing informed consent. 2. Provide written informed consent for the trial, including willingness to comply with all study related requirements. 3. Histologically or cytologically confirmed solid tumor. Subjects with more than 1 primary malignancy may be considered upon review with the Sponsor's Medical Monitor. 4. Evidence of disease progression or inadequate response on the last regimen as assessed by the Investigator. 5. Has exhausted all curative options or has a contraindication to approved therapies or generally recognized standard-of-care measures for the subject's cancer. 6. Presence of measurable disease as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 7. Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 8. Has adequate organ functions as defined by the following laboratory parameters at baseline (laboratory parameters outside of these ranges that are deemed clinically insignificant should be discussed with the Medical Monitor): (a) Absolute neutrophil count ≥1.5 x 109/L; (b) hemoglobin ≥9 g/dL; (c) platelet count ≥100,000/mm3; (d) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN); (e) total bilirubin ≤ 1.5 x institutional ULN (exception: subjects with known Gilbert's syndrome and total bilirubin ≤3.0 x ULN at screening or anytime during the prior 6 months are eligible); (f) c) adequate renal function defined as calculated creatinine clearance \>60 mL/min using the Cockcroft-Gault Method (Appendix 3); (g) acceptable coagulation parameters including international normalized ratio (INR) \<1.5 and partial thromboplastin time (PTT) ≤ institutional ULN; (h) serum albumin ≥3.0 g/dL. 9. Left ventricular ejection fraction of ≥50% as assessed by echocardiogram or MUGA scan. 10. Adequate washout from the following prior to first dose of study therapy: Palliative radiation ≥ 2 weeks; chemotherapy or targeted therapy ≥ 3 weeks or 5 half-lives; biologic therapy ≥ 4 weeks. 11. Resolution to Grade ≤1 by the National Cancer Institute CTCAE, Version 5.0 (NCI-CTCAE v 5.0) of all clinically significant toxic effects of prior therapies. 12. Female subjects: A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: (a) Not a woman of childbearing potential (WOCBP); (b) WOCBP who agrees to follow the contraceptive guidance during the study treatment period and for at least 120 days after the last dose of study treatment. 13. Female subject of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving any dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 14. Male subject is eligible to participate if he agrees to follow the acceptable contraceptive guidance during the study treatment period and for at least 120 days after the last dose of study treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The number of subjects with adverse events based on the Common Terminology Criteria for Adverse Evens (CTCAE) v5.0 following treatment with DT2216. | 28 days | The incidence of adverse events will be the number of subjects with an adverse event divided by the total number subjects. |
| The number of subjects with adverse events of different grades based on the CTCAE v5.0 | 28 days | The severity will be based on the grading of adverse events as described in the CTCAE v5.0 |
| The number of subjects with dose limiting toxicity (DLT) of DT2216. | 28 days | DLT's will be defined by any of the following: Any Grade 5 toxicity on the CTCAE CTCAE v5.0 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with clinically significant hemorrhage CTCAE Grade 4 neutropenia lasting \>7 days Febrile Neutropenia, defined as absolute neutrophil count (ANC) \<1000/mm3 with a single temperature of \>38.3°C (101°F) or a sustained temperature of \>38°C (100.4°F) for \>1 hour Grade 3 thrombocytopenia that is clinically uncomplicated and lasting ≥7 days. CTCAE Grade 4 non-hematologic toxicity of any duration CTCAE Grade 3 non-hematologic toxicity, except nausea, vomiting and/or diarrhea lasting ≤3 days or laboratory abnormalities that return to baseline within ≤3 days with or without medical intervention Changes in liver enzymes consistent with Hy's law indicative of drug-induced hepatocellular injury |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The measurement of levels of BCL-XL in peripheral blood mononuclear cells | 28 days | Levels of BCL-XL will be measured in peripheral blood mononuclear cells |
| The measurement of Cmax of DT2216 following intravenous administration | 28 days | The Cmax will be based on blood levels following intravenous administrration of DT2216. |
| The number of subjects who have oncological responses to DT2216 based on the RECIST 1.1 criteria. | One year | The response rate to DT2216 will be determined at various time points following administration of DT2216 based on the Response Evaluation Criteria in Solid Tumors 1.1. |
| The measurement of platelet counts following administration of DT2216 | 28 days | Platelet counts will be determined at various time points after administration of DT2216 |
| The measurement of the half-life of DT2216 following intravenous administartion | 28 days | The half-life will be based on blood levels of DT2216 following intravenous administration. |
| The measurement of the clearance of DT2216 following intravenous administration. | 28 days | The clearance of DT2216 will be based on blood levels of DT2216 following intravenous administration |
Countries
United States
Outcome results
None listed