2321GCCC: CRD3874-SI in Patients with Relapsed/refractory AML

Inclusion Criteria:

• Male or female age ≥ 18 years at the time of signing the ICF

• Able to understand and willing to provide written informed consent

• Willing to comply with clinical study instructions and requirements.

• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (Appendix 1).

• Pathologically confirmed diagnosis of AML by 2022 International ConsensusClassification of Myeloid Neoplasms and Acute Leukemias criteria (2)

• AML may be de novo, following a prior hematologic disorder including myelodysplasticsyndrome or Philadelphia chromosome-negative myeloproliferative neoplasm, and/ortherapy-related

• Patients must have relapsed/refractory AML, with any prior therapies and any numberof prior therapies, and have no further standard therapies available.

• Any prior therapy must have been completed ≥2 weeks prior to Day 1 of treatment onstudy, and all treatment-related adverse events (except alopecia) should haverecovered to <Grade 1.

• Hematologic abnormalities that are thought to be primarily related to leukemia arenot considered to be toxicities and do not need to resolve to <Grade 1.

• Myeloid growth factors must have been stopped ≥1 week (filgrastim) or ≥2 weeks (pegfilgrastim) before starting study treatment.

• Prior autologous hematopoietic stem cell transplantation is allowed.

• Prior allogeneic hematopoietic stem cell transplantation is also allowed, ifpatients are ≥60 days from stem cell infusion, have no evidence of graft-versus-hostdisease (GVHD) >Grade 1, and are >4 weeks off calcineurin therapy and ≥2 weeks offall immunosuppressive therapy.

• Peripheral blast count must be <50 × 109/L. Hydroxyurea is permitted for blast countcontrol before starting study treatment, but must be stopped ≥24 hours beforestarting study treatment. It may be reintroduced per physician decision if >50 × 109/L blasts recur during treatment Cycle 1 and managed per physician decision.

• Patients with other malignancies are allowed, if other malignancies are inactive andnot requiring concurrent therapy except hormonal therapy for stable breast orprostate cancer.

• Aspartate aminotransferase (AST) must be <2.5 x Upper Limit Normal (ULN), alanineaminotransferase (ALT) <2.5 x ULN and total serum bilirubin <1.5 x ULN unlessthought due to hemolysis or Gilbert's Syndrome.

• Adequate renal function as defined by calculated creatinine clearance (CrCl) >60ml/minute by the Cockcroft-Gault formula

• Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram (2D-ECHO)

• Life expectancy of at least three months at screening, according to theInvestigator's opinion

• Women of childbearing potential (defined as a sexually mature female who has notundergone a hysterectomy or bilateral oophorectomy or who has not been naturallypostmenopausal for at least 24 consecutive months) must have a negative serum orurine pregnancy test within 7 days of study entry.

• Women of childbearing potential and sexually active men with female partners ofchildbearing potential must agree to use effective contraception, includingabstinence or two forms of contraception, during study treatment and for four weeksafter the last dose odf study drug.

Exclusion Criteria:

• Acute promyelocytic leukemia

• Blast phase of chronic myeloid leukemia

• Known active central nervous system leukemia

• Concurrent chemotherapy, radiation therapy, immunotherapy or other investigationalagents

• Active, uncontrolled infection

• Uncontrolled intercurrent illness including, but not limited to, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, orpsychiatric illness/social situations that would limit compliance with studyrequirements in the investigator's judgment

• Malignancies other than AML requiring active therapy except hormonal therapy forstable breast or prostate cancer

• Active autoimmune disease other than vitiligo, type 1 diabetes, or controlledhypothyroidism

• Interstitial lung disease or any disease requiring supplemental oxygen, or historyof pneumonitis or pulmonary fibrosis from any cause

• Known prior severe hypersensitivity to an investigational product or any componentof the study drug therapy's formulations including polyethylene glycol (PEG;National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]v5.0 Grade ≥ 3)

• Prior chemotherapy or targeted small molecule therapy within 3 weeks, anticancermonoclonal antibody within four weeks or five half-lives, if shorter, or radiationtherapy within 2 weeks prior to the first CRD3874-SI infusion prior to study Day 1,or not recovered (i.e., Grade ≤ 1 or at baseline) from AE due to a previouslyadministered agent (Note: Alopecia is acceptable. If participant received majorsurgery, they must have recovered adequately from the toxicity and/or complicationsfrom the intervention prior to starting study therapy)

• Prior organ transplantation, other than allogeneic or autologous hematopoietic stemcell transplantation.

• Currently participating in a study and receiving study therapy, or participated in astudy of an investigational agent and received study therapy or used aninvestigational device within 4 weeks of the first dose of treatment or 5half-lives, whichever is longer.

• Received a live vaccine within 30 days of the planned start of study drug. (Note:Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines and are not allowed.)

• Evidence of clinically significant immunosuppression including the following:

• Primary immunodeficiency state such as SCID

• Concurrent opportunistic infection

• Receiving systemic immunosuppressive therapy (>2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within seven days prior to enrollment. Inthe setting of non-immune mediated indications for use, chronic/active low dosesteroid use (equivalent to ≤ 10 mg/day prednisone) may be permitted at thediscretion of the Principal Investigator (Note: Other steroid formulations orsteroid use for other indications may be permitted and include: 1) Intranasal,inhaled, ocular, or topical steroids, or local steroid injection (e.g.,intra-articular injection); 2) Systemic corticosteroids at physiologic doses ≤ 10mg/day of prednisone or equivalent; 3) Steroids as premedication forhypersensitivity reactions (e.g., CT scan premedication)

• History or evidence of symptomatic autoimmune disease (e.g., pneumonitis,glomerulonephritis, vasculitis, or other), or history of active autoimmune diseasethat has required systemic treatment (i.e., use of corticosteroids,immunosuppressive drugs or biological agents used for treatment of autoimmunediseases) in past two years prior to enrollment (Note: Replacement therapy [e.g.,thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency] is not considered a formof systemic treatment for autoimmune disease.)

• Evidence of clinically significant interstitial lung disease, history ofinterstitial lung disease, or active, noninfectious pneumonitis related to priorimmunotherapy treatment

• Uncontrolled medical condition including current active infection requiring systemictherapy or symptomatic congestive heart failure (CHF) within six months that in theInvestigator's opinion compromises the ability of the participant to complete allstudy-related requirements safely

• Mean resting corrected QTcF interval ≥ 470 ms on a 12-lead electrocardiogram (ECG)for males and females

• History of unstable or deteriorating cardiovascular disease within the previous sixmonths prior to screening, including but not limited to the following:

• Unstable angina or myocardial infarction (MI)

• Cerebrovascular accident (CVA)/stroke

• CHF (New York Heart Association [NYHA] Class III or IV)

• Uncontrolled clinically significant arrhythmias

• Known to be positive for active Hepatitis B (HBV; Hepatitis B surface antigen [HBsAg] reactive with detectable HBV DNA), or Hepatitis C (HCV; detectable HCV RNA [qualitative])

• Patients with chronic HBV (positive HBsAg and/or Hepatitis B core antibody [HBcAb] and negative HBV DNA by polymerase chain reaction [PCR]) are eligiblefor this study if they are on suppressive antiviral therapy and deemed safe bya gastroenterologist

• Patients who are HCV antibody (Ab)-positive but HCV RNA-negative due to priortreatment or natural resolution will be considered eligible

• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) diseasethat is not controlled. Individuals known to be HIV-positive will be consideredeligible if all the following criteria are met:

• Established antiretroviral treatment (ART) for at least four weeks and have anHIV viral load less than 400 copies/mL prior to enrollment

• CD4+ T-cell counts ≥ 350 cells/uL

• No opportunistic infection within the past 12 months

• No known history of active tuberculosis (TB)

• The presence of a concurrent active malignancy that in the opinion of theInvestigator could compromise the conduct of the study or interfere with determiningthe outcomes of the study objectives

• Women who are pregnant or breastfeeding

• Expecting to conceive or father children within the projected duration of the study,starting with the prescreening or screening visit through three months after thelast dose of study treatment(s)