A Phase 1, Dose Escalation and Cohort Expansion Study to Evaluate the Safety, Pharmacokinetics and Clinical Activity of DT2216, an Antiapoptotic Protein Targeted Degradation Compound, in Patients With Relapsed/Refractory Malignancies
Overview
- Phase
- Phase 1
- Intervention
- DT2216
- Conditions
- Solid Tumor
- Sponsor
- Dialectic Therapeutics, Inc
- Enrollment
- 20
- Locations
- 3
- Primary Endpoint
- The number of subjects with adverse events based on the Common Terminology Criteria for Adverse Evens (CTCAE) v5.0 following treatment with DT2216.
- Status
- Completed
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adults aged 18 years or older on the day of signing informed consent.
- •Provide written informed consent for the trial, including willingness to comply with all study related requirements.
- •Histologically or cytologically confirmed solid tumor. Subjects with more than 1 primary malignancy may be considered upon review with the Sponsor's Medical Monitor
- •Evidence of disease progression or inadequate response on the last regimen as assessed by the Investigator.
- •Has exhausted all curative options or has a contraindication to approved therapies or generally recognized standard-of-care measures for the subject's cancer.
- •Presence of measurable disease as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •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.
- •Left ventricular ejection fraction of ≥50% as assessed by echocardiogram or multi-gated acquisition (MUGA) scan.
- •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.
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
- •Adults aged 18 years or older on the day of signing informed consent.
- •Provide written informed consent for the trial, including willingness to comply with all study related requirements.
- •Histologically or cytologically confirmed solid tumor. Subjects with more than 1 primary malignancy may be considered upon review with the Sponsor's Medical Monitor.
- •Evidence of disease progression or inadequate response on the last regimen as assessed by the Investigator.
- •Has exhausted all curative options or has a contraindication to approved therapies or generally recognized standard-of-care measures for the subject's cancer.
- •Presence of measurable disease as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- •Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Arms & Interventions
DT2216
DT2216 will be administered by intravenous infusion over 30 minutes twice weekly on a continuous basis. Each treatment cycle will be 28 days in duration. The starting dose of DT2216 will be 0.04 mg/kg and will escalate by 100% increments for the first 5 treatment groups. Thereafter, if additional dose escalations are required, escalation will follow a modified Fibonacci scheme. Treatment may continue for up to 1 year.
Intervention: DT2216
Outcomes
Primary Outcomes
The number of subjects with adverse events based on the Common Terminology Criteria for Adverse Evens (CTCAE) v5.0 following treatment with DT2216.
Time Frame: 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
Time Frame: 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.
Time Frame: 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 Outcomes
- The measurement of the half-life of DT2216 following intravenous administartion(28 days)
- The measurement of the clearance of DT2216 following intravenous administration.(28 days)
- The measurement of Cmax of DT2216 following intravenous administration(28 days)
- The measurement of levels of BCL-XL in peripheral blood mononuclear cells(28 days)
- The measurement of platelet counts following administration of DT2216(28 days)
- The number of subjects who have oncological responses to DT2216 based on the RECIST 1.1 criteria.(One year)