SMARCA4/2 Inhibitor for POU2F3-Positive SCLC

This is a single-arm, phase II clinical trial evaluating the efficacy and safety of FHD-286, a SMARCA4/2 inhibitor, in participants with extensive-stage small cell lung cancer and documented POU2F3 expression, who have progressed after prior platinum-based therapy.

FHD-286 has not been approved by the FDA or any other regulatory authorities around the world for the treatment of POU2F3 expressing small cell lung cancer.

The study includes clinical examinations, medical history collection, performance status evaluation, vital signs and weight checks, tumor assessments by one or more of the following tools: Computerized Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, or Positron Emission Tomography (PET) scans, blood tests, pregnancy test for women of childbearing potential, Electrocardiogram (ECG), Echocardiogram (ECHO) test, tumor tissue sample, and biobanking.

It is expected that about 20 people will take part in this research study.

Foghorn Therapeutics, Inc. is supporting this research study by providing study drug and partial funding. FHD-286 has not been approved by the FDA or any other regulatory authorities around the world for the treatment of POU2F3 expressing small cell lung cancer.

It is expected that about 20 people will take part in this research study Foghorn Therapeutics, Inc. is supporting this research study by providing study drug and partial funding.

Inclusion criteria

• Adult age l8 years or older, who have provided written informed consent.
• Histologically or cytologically confirmed extensive stage SCLC with documented disease progression or recurrence after prior platinum-based therapy with or without checkpoint inhibitor.
• Positive >50% POU2F3 expression by IHC staining.
• Participants must have measurable disease based on RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or l.
• Participants must meet the following organ and marrow function criteria:

• leukocytes ≥2,000/mcL
• absolute neutrophil count (ANC) ≥1,000/mcL
• platelets ≥50,000/mcL
• hemoglobin ≥9 g/dL
• total bilirubin ≤ 1.5 institutional upper limit of normal (ULN); Unless considered due to advanced malignancy involvement or Gilbert syndrome, with PI approval
• AST(SGOT)/ALT(SGPT) ≤3.0 × institutional ULN; Unless considered due to advanced malignancy involvement, with PI approval
• ALP ≤3.0 × institutional ULN; Unless considered due to advanced malignancy involvement, with PI approval
• prothrombin time ≤1.5 × institutional ULN or international normalized ratio (INR) ≤1.4
• activated partial thromboplastin time (aPTT) ≤1.5 × institutional ULN; PI approval is required for a participant receiving anticoagulation therapy for treatment of a stable medical condition
• creatinine ≤ 1.5 institutional ULN OR glomerular filtration rate (GFR) ≥40 mL/min/1.73 m2
• left ventricular ejection fraction ≥40% by ECHO
• no known portal vein thrombosis
• adequate cardiovascular, respiratory, and immune system function, in the opinion of the investigator
• Agree to abide by dietary and other considerations required during the study
• The effects of FHD-286 on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) sexually active with male partners and fertile men sexually active with WOCBP must agree to use dual contraceptive measures (hormonal or barrier method of birth control; abstinence; condom), beginning at the screening visit and until 90 days after taking the last dose of FHD-286. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Participants must agree to refrain from donating sperm/ova from the screening visit through 90 days after the last dose of FHD-286.
• The potential risk to fertility posed by FHD-286 is unknown. It is recommended that subjects discuss options for fertility preservation with their doctor before starting treatment.
• See Section 5.2.2 for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents.
• Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
• Note: Non-child-bearing potential is defined as follows:

• >45 years of age and has not had menses for >1 year. Participants who have been amenorrhoeic for <2 years without history of a hysterectomy or bilateral oophorectomy must have a follicle-stimulating hormone value in the postmenopausal range upon screening evaluation.
• Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
• Ability to understand and the willingness to sign a written informed consent document.
• Must be willing and able to swallow pills

Exclusion criteria

• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.
• Participants who are receiving any investigational therapy
• Symptomatic brain metastases (untreated, asymptomatic brain metastases are eligible if size <6 mm).
• Participants receiving any medications or substances that are strong inhibitors, strong inducers, or sensitive CYP3A substrates (with narrow therapeutic indices) of CYP3A enzymes are ineligible (see also Section 3.3).

• Individuals must have stopped treatment with strong CYP3A inhibitors at least 1 week or 5 half-lives, whichever is longer, before the first dose of study drug. Strong CYP3A inhibitors may be permitted with PI approval; the FHD-286 dose should be reduced to 1.5 mg QD when a strong CYP3A inhibitor is in use.
• Individuals must have stopped treatment with strong CYP3A inducers at least 2 weeks or 5 half-lives, whichever is longer, before the first dose of study drug. Strong CYP3A inducers may be permitted with PI approval.
• Stable doses of immunosuppressants that are sensitive CYP3A substrates with narrow therapeutic indices may be permitted with PI approval.
• Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• Taking proton pump inhibitors (PPIs). Administration of PPIs must be stopped or switched to another acid-reducing agent within 7 days before study entry. If it is medically necessary to administer PPIs concomitantly with FHD-286, this may be permitted with PI approval.
• Taking clinically significant or increasing doses of systemic steroid therapy or any other systemic immunosuppressive medication. The use of a stable dose of such therapies may be permitted with PI approval. Local/targeted therapies, eg, inhaled or topical steroids, are acceptable. Appropriate steroid replacement to manage endocrine toxicities resulting from prior systemic anticancer therapy is acceptable.
• Currently pregnant. Female participants must have a negative urine pregnancy test within 7 days prior to taking study treatment if of childbearing potential.
• Currently breastfeeding.
• Planning to become pregnant within 1 year after start of study treatment.
• Any active cancer requiring systemic treatment or prior cancer treated within past 2 years (excluding non-melanoma skin cancer, DCIS, low risk prostate cancer not requiring treatment, superficial bladder cancer, or other low risk cancers after communication with PI).
• Timing requirements with respect to prior therapy and surgery:

• Radiotherapy: At least 2 weeks must have elapsed since last radiotherapy
• Surgery: Participant must be recovered from any clinically relevant effects of any prior surgery
• Any active infection requiring treatment (excluding HIV with undetectable viral load). Active hepatitis B (defined by presence of Hep B sAg) or C is not eligible, unless the individual has a sustained viral response to HCV treatment or immunity to prior HBV infection.
• Uncontrolled intercurrent illness that could limit life expectancy or ability to complete study. This includes, but is not limited to:

• QTcF >470 msec or other factors that increase the risk of QTc prolongation. Participants with QTcF >470 msec and bundle branch block and/or pacemaker rhythm may be enrolled with approval from PI.
• New York Heart Association class III/IV congestive heart failure of
• Psychiatric illness/social situations that would limit compliance with study requirements
• Any other prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the individual or impair the assessment of study results
• GI dysfunction that would preclude adequate absorption, distribution, metabolism, or excretion of FHD-286
• Known hypersensitivity to any component of the FHD-286 formulation
• Prior treatment with any SMARCA2/4 inhibitor, including FHD-286