MC# 21-26 - A Phase I, 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 Patients with Relapsed or Refractory Malignancies
Disease Type(s): Solid Tumor
Drug Classification(s): Small Molecule, Targeted Therapy
Molecular Target(s): BCL-XL
Mechanism of Action
DT2216 is a small molecule degrader of BCL-XL protein working as molecules called proteolysis targeting chimeras (PROTACs). PROTACs are bivalent small molecules containing a pharmacophore that recognizes the target protein linked to a second pharmacophore that binds to a specific E3 ubiquitin ligase.
In this study, the sponsor and investigators want to learn:
- How much of DT2216 can be given with an acceptable level of side effects
- About the safety and tolerability of DT2216
- How much of DT2216 is absorbed into the blood and how fast it is remove
- How proteins that indicate the status of your disease are affected with use of DT2216
- If research tests can be used in the future to predict who will benefit from DT2216
- If DT2216 prevents or delays tumor growth
- 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. Patients with more than 1 primary malignancy may be considered upon review with the Sponsor’s Medical Monitor.
- Evidence of disease progression 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 patient’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: patients 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; (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 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
- 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
- Female patients: A female patient 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
- Female patient 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.
- Male patient 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
- Received any BCL-XL directed therapy
- Experienced involuntary weight loss >10% over the past 3 months
- Administration of any blood products within the 30 days preceding the planned administration of study therapy
- History of clinically significant bleeding and/or bleeding predisposition
- Significant liver cirrhosis defined as Child-Pugh Class B or C
- Concurrent administration of medications or foods that are strong inhibitors or inducers of cytochrome P450 3A (CYP3A). Strong CYP3A inhibitors and inducers should be discontinued at least 2 weeks prior to the first dose of DT221.
- Patients with HIV on anti-retroviral therapy
- Known active central nervous system (CNS) metastases/and or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable without evidence of progression via imaging for at least 4 weeks prior to first dose of study therapy, and there is no evidence of neurological symptoms. Carcinomatous meningitis is excluded regardless of clinical stability.
- Requiring anticoagulation for any reason (patients who are on anticoagulants during the screening period and are candidates for discontinuation can be considered)
- Prior organ transplantation including allogeneic or autologous stem-cell transplantation or other cellular therapies (e.g. CAR-T)
- Major surgery <4 weeks prior to first dose of study therapy
- Growth factor use <4 weeks prior to first dose of study therapy
- Participation in another research study involving receipt of an investigational product <4 weeks prior to first dose of study therapy. If the half-life of the investigational study is known, a shorter interval may be appropriate and should be discussed with the Sponsor’s Medical Monitor. Participants who have entered the follow-up phase of an investigational study may be eligible as long as it has been 4 weeks after the last dose of the previous investigational agent.
- Active autoimmune disease or history of chronic recurrent autoimmune disease, requiring systemic treatment for the past 2 years (i.e. disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (thyroxine, insulin, or physiological corticosteroid replacement for either adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
- Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment (note: topical, inhaled, nasal and ophthalmic steroids are permitted)
- Known active hepatitis B (e.g., HBsAg reactive), hepatitis C (e.g., HCV RNA [qualitative] is detected)
- Active infection with human immunodeficiency virus (HIV) except: (a) Patient is off antiretroviral therapy (ART) for at least 4 weeks and agrees to adhere to ART during study therapy; (b) HIV viral load of < 400 copies per milliliter (/mL) at Screening (or undetectable per local criteria); (c) CD4 counts ≥200/microliter
- Active infection requiring systemic therapy
- Known allergy to any component of the study treatment formulation(s)
- Known history of marked prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >470 milliseconds (ms) using Fredericia’s QT correction formula
- History of additional risk factors for Torsade de Pointes (including heart failure, hypokalemia, family history of Long QT Syndrome, and use of concomitant medications that prolong the QT/QTc interval
- Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment
- Clinically significant cardiovascular disease including: History of myocardial infarction within 6 months prior to day 1 of study therapy, symptomatic congestive heart failure (New York Heart Association Class II to IV), troponin levels consistent with myocardial infarction as defined according to American College of Cardiologists guidelines, unstable angina, or serious cardiac arrhythmia requiring treatment, uncontrolled angina within 3 months of day 1 of study therapy, uncontrolled hypertension
- COVID-19 diagnosis within 3 months of first dose of study drug
- Any other history of clinically significant and ongoing chronic respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder or any other medical or psychiatric condition that in the opinion of the Investigator will significantly increase the safety risk for the patient or confound the interpretation of the study data
- History of alcohol or drug abuse within 6 months of first dose of study therapy
- In the opinion of the Investigator, participant has rapidly progressing disease, OR has life expectancy <3 months, OR would be unable to receive at least 1 study treatment
- Dallas, TX - Mary Crowley Cancer Research - Medical City