IRB Study Number 23-450
Status Recruiting
Institute Taussig Cancer Institute
Description
5.1.1 Primary Objective
To evaluate safety and tolerability and establish the RP2D of GDX012 in adult patients with
relapsed or refractory (R/R) AML.
5.1.2 Secondary Objective
To evaluate disease response and efficacy in adult patients with R/R AML who received
GDX012.
5.1.3 Exploratory Objectives
To evaluate the cellular kinetics (expansion and persistence) of GDX012 in blood.
To evaluate the immunogenicity of GDX012.
To evaluate the presence of GDX012 in bone marrow.
To explore the relationship between exposure and response (safety, disease response, and product attributes) using exposure/response analysis and cellular kinetic (CK)/pharmacodynamic (PD) modelling, where feasible.
To evaluate the level of cytokines and soluble factors in blood after GDX012 administration.
To evaluate any correlations between exploratory biomarkers, disease response, and safety of GDX012.
To assess healthcare resource utilization.
To establish health utility.
Inclusion Criteria
Aged ≥18 years at the time of signing the informed consent.
Total body weight of ≥40 kg.
Must have pathologically confirmed R/R AML per 2022 International Consensus Classification (ICC) classification, as follows:
a. Relapsed AML is defined as the appearance of ≥5% blasts in the BM or peripheral blood at any time after achieving a CR, CRh, CRi, or MLFS.
b. Refractory AML is defined as failure to achieve a CR, CRh, CRi, or MLFS after 1 of the following regimens:
i. Two courses of intensive induction chemotherapy, eg, 7+3 (7 days of cytarabine plus 3 days of anthracycline); mitoxantrone, etoposide, and cytarabine; high-dose cytarabine; etc. (where 5+2 given on Days 14 to 21 for persistent leukemia on Day 14 will count as a second induction or 1 induction attempt is required for patients >60 years of age.
ii. At least 2 cycles of hypomethylating agent (HMA) or low-dose, cytarabine-based combination regimen including, but not limited to, venetoclax or other B-cell lymphoma 2 (BCL2) inhibitors.
iii. At least 4 cycles of HMA monotherapy.
During dose escalation, patients must be ineligible for HSCT due to comorbid condition, inability to receive HSCT conditioning, lack of an available donor, patient having declined procedure after documented discussion of the risks and benefits, or investigator considers it not to be in the best interest of the patient.
Must have an anticipated life expectancy of >3 months before lymphodepletion.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix G).
Left ventricular ejection fraction of ≥40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
Adequate organ function as indicated by the laboratory values below: (See protocol)
Female patients who:
a. Are postmenopausal for at least 1 year before the screening visit, or
b. Are surgically sterile, or
c. If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through at least 12 months following GDX012 administration, or
d. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female and male condoms should not be used together, and
e. Agree not to breastfeed a baby or donate an egg or eggs (ova) during the study and until at least 12 months following GDX012 administration.
- Male patients, even if surgically sterilized (ie, status postvasectomy), who:
a. Agree to practice effective barrier contraception from the time of signing the informed consent through at least 12 months following GDX012 administration, or
b. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception). Female and male condoms should not be used together, and
c. Agree not to donate sperm during the study and at least until 12 months following GDX012 administration.
Voluntary written consent before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Willingness and ability to comply with scheduled visits and study procedures.
Exclusion Criteria
Diagnosis of acute promyelocytic leukemia.
Has received or plans to receive any of the following excluded therapy/treatment within the specified timeframe before lymphodepleting chemotherapy:
a. Cytotoxic chemotherapy or immunotherapy within 2 weeks before lymphodepletion. Hydroxyurea is allowed up to 2 days before start of lymphodepletion. Intrathecal chemotherapy is allowed up to 7 days before lymphodepletion. Hypomethylating agents are allowed up to 10 days before lymphodepletion.
b. Corticosteroids or any other immunosuppressive therapy within 2 weeks before lymphodepletion, with exception of the following:
i. Use of inhaled, topical, intranasal, ocular, or intra articular corticosteroids.
ii. Physiological doses of replacement steroids (eg, for adrenal insufficiency) not to exceed 10 mg/day of prednisone or equivalent.
c. Investigational treatment or interventional clinical trial within 2 weeks or 5 half lives (if known), whichever is longer, before lymphodepletion.
d. Major surgery within 4 weeks before lymphodepletion (patients must have fully recovered from any surgery related toxicities).
e. Donor lymphocyte infusion within 30 days before lymphodepletion for patients who have previously undergone HSCT.
Prior allogeneic HSCT within 3 months of signing ICF or with ongoing requirement for systemic graft-versus-host therapy.
Has received prior gene or modified cell therapy (eg, CAR-T or CAR-NK).
WBC >20,000/μL or evidence of rapid disease progression that would prevent completion of at least 1 dose cycle. (Cytoreductive therapies including leukapheresis or hydroxyurea are allowed.)
Ongoing nonhematologic toxicity from prior anticancer therapy that has not recovered to Grade ≤1 before enrollment (except for nonclinically significant toxicities, eg, alopecia, vitiligo), with the exception of patients with Grade 2 toxicities that are deemed stable or irreversible (eg, hypothyroidism), who may be enrolled at the investigator’s discretion.
Known hypersensitivity to fludarabine, cyclophosphamide, or other agents, or excipients used in the study.
History of chronic or recurrent (within the last year before screening) severe autoimmune or immune-mediated disease requiring steroids or other immunosuppressive treatments, including antitumor necrosis factor agents.
Active central nervous system involvement (eg, symptomatic, central nervous system [CNS] 3, or radiologically detected disease). Patients with history of CNS leukemia which has been adequately treated will be considered eligible.
History or presence of active/clinically relevant CNS disorder such as seizure, encephalopathy, cerebrovascular ischemia/hemorrhage, severe dementia, cerebellar disease, or any autoimmune disease with CNS involvement. For CNS disorders that recover or are in remission, patients without recurrence within 2 years of planned study enrollment may be included.
History of malignancy are excluded with the following exceptions:
a. Patients with a history of treated, non-melanoma skin cancer, or in situ carcinoma of cervix, bladder, or breast who have received curative treatment anytime before screening.
b. Patients with low-grade, early stage prostate cancer (eg, Gleason score ≤6, stage 1 or 2) with no requirement for therapy anytime prior to enrollment.
c. Any other malignancy status post curative intent therapy and in remission without treatment for ≥2 years before enrollment.
d. Patients on adjuvant endocrine therapy for localized hormone receptor positive breast cancer for ≥2 years before enrollment.
- Uncontrolled intercurrent illness including, but not limited to, the following:
a. Ongoing or active infection (eg, requiring systemic antimicrobial therapy for treatment of infection within 5 days before start of lymphodepletion). Patients on long-term antimicrobial therapy with no evidence of active disease and those on prophylactic antimicrobials are not excluded.
b. Clinically significant cardiac disease defined by congestive heart failure New York Heart Association Class 3 or Class 4.
c. Clinically significant (symptomatic) cardiac arrhythmias (eg, sustained ventricular tachycardia, second- or third-degree atrioventricular block without a pacemaker, or circulatory collapse arrhythmia requiring therapy).
d. Acute coronary syndrome (unstable angina or myocardial infarction) in the last 6 months. Patients with medically controlled angina may be enrolled.
e. Interstitial lung disease causing them to be oxygen dependent.
- Active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) as defined below:
a. Positive serology for HIV.
b. Positive hepatitis B surface antigen (HBsAg) test and/or positive HBV deoxyribonucleic acid (DNA) test. Patients who are HBsAg negative but are hepatitis B core antibody positive must have undetectable HBV DNA and receive prophylaxis against viral reactivation. Prophylaxis should be initiated before lymphodepleting therapy and continued for 6 months.
c. Positive HCV RNA test. Patients who are hepatitis C antibody positive will be screened for HCV RNA by any reverse transcription PCR or branched DNA assay. If hepatitis C antibody is positive, eligibility will be determined based on a negative screening RNA value.
Clinically active severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) viral infection defined by prior positive test or presumptive symptoms without demonstration of a negative test.
Female patients who are lactating and breastfeeding.
Female patients who have a positive serum pregnancy test.
Any other medical, psychological, or social condition that, in the opinion of the principal investigator (PI), would contraindicate the patient's participation in the clinical study due to safety or compliance with clinical study procedures.
