A Study of CRD3874-SI in People With Leukemia

A Phase 1 Study of the STING Agonist CRD3874-SI for Relapsed and Refractory Acute Myeloid Leukemia

The purpose of this study is to find out whether CRD3874-SI is a safe treatment for participants with acute myeloid leukemia (AML).

Inclusion Criteria:

• Documentation of Disease

  o Participant has relapsed or refractory acute myeloid leukemia, defined as bone marrow blasts ≥ 5%, and/or reappearance of blasts in the blood in at least 2 peripheral blood samples at least one week apart, and/or development of extramedullary disease; or, no CR, CRh or CRi at response assessment after at least 1 line of therapy, as defined by standardized European LeukemiaNet 2022 Criteria. Patients must have failed treatment with available therapies known to be active for treatment of their AML.

• Participant must be ≥ 18 years of age at the time of signing the informed consent form (ICF).

• Participant must weigh at least 40 kg

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status score 0-2 (See Appendix I for performance status criteria)

• For patients with known HIV, HBV, and/or HCV infection [HIV, HBV, and HCV testing do not need to be performed as part of the study; the below language provides guidelines for inclusivity of patients with known HIV, HBV, and/or HCV infection]:

  • HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• Required Organ Function

  • Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN, unless considered due to leukemic organ involvement.
  • Serum total bilirubin < 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis, leukemia organ involvement or Gilbert's syndrome.
  • Calculated creatinine clearance (CrCl) ≥ 60 mL/min by Cockcroft-Gault formula or CKD-EPI 2021 or estimated glomerular filtration rate 60 mL/min or greater based on local institutional practice for age-appropriate determination (e.g, Schwartz formula for pediatric patients or Cockcroft Gault formula for adults).
  • Adequate cardiac function defined as ejection fraction of ≥ 50% by echocardiogram.

Exclusion Criteria:

• Participants with acute promyelocytic leukemia

• Participants with isolated myeloid sarcoma

• Blast phase of chronic myeloid leukemia

• Known active central nervous system leukemia

• Participants with immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, disseminated intravascular coagulation, or uncontrolled tumor lysis syndrome.

• Participant has presence of any other condition that may increase the risk associated with study participation, and in the opinion of the treating investigator, would make the patient inappropriate for entry into the study.

• Participants with concurrent other malignancy that will confound interpretation of study endpoints.

• Participants who have received other anti-leukemia therapy within 5 half-lives of the agent or 14 days, whichever is sooner, prior to study treatment and if toxicity related to said agent has not resolved; exceptions of acceptable concomitant therapies are listed below

  1. Concomitant cytoreductive therapy in the form of hydroxyurea, corticosteroids, or cytarabine is permitted.
  2. Concomitant therapy in the form of intrathecal chemotherapy for CNS treatment, is permitted.
  3. Radiation therapy is not permitted except for localized palliative radiation to focal lesions after discussion with the Medical Monitor for patients who have progressed but remain on the study due to perceived clinical benefit per Investigator assessment

• Participants with active graft versus host disease (GVHD) of grade 2 or higher requiring systemic treatment. Skin GVHD solely managed with topical corticosteroids would not be exclusionary.

• Known prior severe hypersensitivity to an investigational product or any component of the study drug therapy's formulations including polyethylene glycol (PEG; National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v6.0 Grade ≥ 3)

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

• Received a live vaccine within 30 days of the planned start of study drug.

  a. (Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.)

• Evidence of clinically significant immunosuppression including the following:

  a. Primary immunodeficiency state such as SCID b. Concurrent opportunistic infection c. Receiving systemic immunosuppressive therapy (>2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within seven days prior to enrollment. In the setting of non-immune mediated indications for use, chronic/active low dose steroid use (equivalent to ≤ 10 mg/day prednisone) may be permitted at the discretion of the Principal Investigator i. (Note: Other steroid formulations or steroid 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 ≤ 10 mg/day of prednisone or equivalent; 3) Steroids as premedication for hypersensitivity 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 disease that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive drugs or biological agents used for treatment of autoimmune diseases) in past two years prior to enrollment

  a. (Note: Replacement therapy [e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency] is not considered a form of systemic treatment for autoimmune disease.)

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

• Participant has significant active cardiac disease within 6 months prior to start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure; acute coronary syndrome (ACS); and/or stroke.

• Participant has QTc interval (i.e., Fridericia's correction [QTcF]) ≥ 470 ms. Patients with a QTcF over 470 ms due to a bundle branch block or a pacemaker may participate in the study with approval of the study principal investigator.

• Participant has active viral infection with human immunodeficiency virus (HIV), or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

• Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally.

• Participant has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).

• Participant with active use of strong or moderate CYP3A4 inhibitors.

• Female participant who is pregnant or lactating.

• Because STING agonist agents impact immune and cellular functioning posing potential risk for impacting normal embryonic development, and because other therapeutic agents used in this trial are known to be teratogenic, participants of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 6 months (females) or 3 months (males) following the completion of study therapy. Male or female participants not willing to comply with contraceptive requirements will be excluded, which adequate contraception (hormonal or barrier method of birth control; abstinence) during study therapy and for 6 months (females) or 3 months (males) following the completion of study therapy