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Trial Title: Testing the Combination of an Anti-cancer Drug, Iadademstat, With Other Anti-cancer Drugs (Atezolizumab or Durvalumab) at Improving Outcomes for Small Cell Lung Cancer

NCT ID: NCT06287775

Condition: Extensive Stage Lung Small Cell Carcinoma
Stage IV Lung Cancer AJCC v8

Conditions: Official terms:
Lung Neoplasms
Small Cell Lung Carcinoma
Carcinoma, Small Cell
Atezolizumab
Durvalumab
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G

Study type: Interventional

Study phase: Phase 1/Phase 2

Overall status: Not yet recruiting

Study design:

Allocation: Randomized

Intervention model: Sequential Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Biological
Intervention name: Atezolizumab
Description: Given IV
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: MPDL 3280A

Other name: MPDL 328OA

Other name: MPDL-3280A

Other name: MPDL3280A

Other name: MPDL328OA

Other name: RG 7446

Other name: RG-7446

Other name: RG7446

Other name: RO 5541267

Other name: RO-5541267

Other name: RO5541267

Other name: Tecentriq

Intervention type: Procedure
Intervention name: Biopsy
Description: Undergo optional tumor biopsy
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: BIOPSY_TYPE

Other name: Bx

Intervention type: Procedure
Intervention name: Biospecimen Collection
Description: Undergo blood sample collection
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: Biological Sample Collection

Other name: Biospecimen Collected

Other name: Specimen Collection

Intervention type: Procedure
Intervention name: Computed Tomography
Description: Undergo CT scan
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: CAT

Other name: CAT Scan

Other name: Computed Axial Tomography

Other name: Computerized Axial Tomography

Other name: Computerized axial tomography (procedure)

Other name: Computerized Tomography

Other name: Computerized Tomography (CT) scan

Other name: CT

Other name: CT Scan

Other name: tomography

Intervention type: Biological
Intervention name: Durvalumab
Description: Given IV
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: Imfinzi

Other name: Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer

Other name: MEDI 4736

Other name: MEDI-4736

Other name: MEDI4736

Intervention type: Procedure
Intervention name: Echocardiography
Description: Undergo ECHO
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: EC

Intervention type: Drug
Intervention name: Iadademstat
Description: Given PO
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: ORY 1001

Other name: ORY-1001

Other name: RG 6016

Other name: RG6016

Other name: RO 7051790

Other name: RO7051790

Other name: trans-N1-((1R,2S)-2-Phenylcyclopropyl)-1,4-cyclohexanediamine

Intervention type: Procedure
Intervention name: Magnetic Resonance Imaging
Description: Undergo MRI
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: Magnetic Resonance

Other name: Magnetic Resonance Imaging (MRI)

Other name: Magnetic resonance imaging (procedure)

Other name: Magnetic Resonance Imaging Scan

Other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance

Other name: MR

Other name: MR Imaging

Other name: MRI

Other name: MRI Scan

Other name: MRIs

Other name: NMR Imaging

Other name: NMRI

Other name: Nuclear Magnetic Resonance Imaging

Other name: sMRI

Other name: Structural MRI

Intervention type: Procedure
Intervention name: Multigated Acquisition Scan
Description: Undergo MUGA
Arm group label: Phase I (iadademstat, atezolizumab, durvalumab)
Arm group label: Phase II Arm II (atezolizumab, durvalumab)
Arm group label: Phase II, Arm I (iadademstat, atezolizumab, durvalumab)

Other name: Blood Pool Scan

Other name: Equilibrium Radionuclide Angiography

Other name: Gated Blood Pool Imaging

Other name: Gated Heart Pool Scan

Other name: MUGA

Other name: MUGA Scan

Other name: Multi-Gated Acquisition Scan

Other name: Radionuclide Ventriculogram Scan

Other name: Radionuclide Ventriculography

Other name: RNV Scan

Other name: RNVG

Other name: SYMA Scanning

Other name: Synchronized Multigated Acquisition Scanning

Summary: This phase I/II trial tests the safety, side effects, and best dose of iadademstat when given together with atezolizumab or durvalumab, and studies the effect of the combination in treating patients with small cell lung cancer that has spread outside of the lung in which it began or to other parts of the body (extensive stage) who initially received standard of care chemotherapy and immunotherapy. Iadademstat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as atezolizumab or durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Adding iadademstat to either atezolizumab or durvalumab may be able to stabilize cancer for longer than atezolizumab or durvalumab alone in treating patients with extensive stage small cell lung cancer.

Detailed description: PRIMARY OBJECTIVE: I. To compare the progression-free survival (PFS) between the combination of iadademstat plus immune checkpoint inhibitor (ICI) versus ICI maintenance alone. SECONDARY OBJECTIVES: I. To compare objective response rate (ORR) and overall survival (OS) between treatment arms. II. To evaluate the safety of combination iadademstat plus ICI. EXPLORATORY OBJECTIVES: I. To assess whether detection of circulating tumor DNA (ctDNA) minimal residual disease correlates with disease progression. II. To assess whether iadademstat impacts the correlation of ICI (atezolizumab or durvalumab) baseline and time varying clearance with clinical outcomes (PFS and OS) and the presence of cachexia. III. To explore exposure response relationships of iadademstat in combination with ICIs. IV. To characterize changes to small cell lung cancer (SCLC) subtype throughout treatment. OUTLINE: This is a phase I dose-escalation study of iadademstat in combination with atezolizumab and durvalumab followed by a randomized phase II study. PHASE I: Patients receive iadademstat orally (PO) on days 1, 8, 15, and 22 or days 1 and 15 of each cycle. Patients also continue receiving their initial ICI treatment, either atezolizumab intravenously (IV) over 30-60 minutes on day 1 of each cycle or durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 arms. ARM I: Patients receive iadademstat PO on days 1, 8, 15, and 22 or days 1 and 15 of each cycle. Patients also continue receiving their initial ICI treatment, either atezolizumab IV over 30-60 minutes on day 1 of each cycle or durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients continue receiving their initial ICI treatment, either atezolizumab IV over 30-60 minutes on day 1 of each cycle or durvalumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. All patients also undergo multi-gated acquisition (MUGA) or echocardiogram (ECHO), brain magnetic resonance imaging (MRI) or brain computed tomography (CT) during screening, and CT scans and blood sample collection throughout the trial. Patients may also undergo an optional tumor biopsy on study. After completion of study treatment, patients are followed up every 3 months for up to 12 months.

Criteria for eligibility:
Criteria:
Inclusion Criteria: - Patients must have histologically or cytologically confirmed small cell lung cancer (SCLC) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions) as ≥ 20 mm (≥ 2 cm) by chest x-ray or as ≥ 10 mm (≥ 1 cm) with CT scan, MRI, or calipers by clinical exam or the shortest axis for nodal lesions as ≥ 15 mm (≥ 1.5 cm) with CT scan - Patients who have been treated with platinum etoposide chemotherapy plus either atezolizumab or durvalumab immunotherapy for 4 cycles with either a radiographic response or stable disease - Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of iadademstat in combination with atezolizumab and durvalumab in patients <18 years of age, children are excluded from this study - Body weight ≥ 50 kg - Patient is able to swallow oral medications - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%). This assessment for eligibility will take place after patients have received 4 cycles of standard of care (SOC) chemotherapy-ICI - Leukocytes ≥ 2,000/mcL - Lymphocyte count ≥ 500/mcL - Absolute neutrophil count ≥ 1,500/mcL - Hemoglobin ≥ 9 g/dL - Platelets ≥ 100,000/mcL - Albumin ≥ 3 g/dL - Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) - Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN unless liver metastases are present, in which case it must be ≤ 5 × ULN - Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 using Chronic Kidney Disease Epidemiology Collaboration (CKD-epi) equation - Human immunodeficiency virus (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 - Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression - Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial - Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Pregnant women are excluded from this study because atezolizumab and durvalumab are monoclonal antibody agents with the potential for teratogenic or abortifacient effects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: - Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy). - Women ≥ 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) - The effects of iadademstat, atezolizumab, and durvalumab on the developing human fetus are unknown. For this reason and because monoclonal antibody agents are known to be teratogenic, women of child-bearing potential and males with females of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 150 days after the last dose of study medication. 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. - Females of childbearing potential must agree to: - Use effective contraception during the trial and 150 days after the end of treatment. - Practice true abstinence during the trial and 150 days after the end of treatment. - Have a negative urine pregnancy test at screening. - Not to donate or freeze egg(s) during the course of this study or within 150 days after receiving their last dose of study drug. - Male patients even if surgically sterilized (i.e., status post-vasectomy) must agree to: - Use effective contraception during the entire study treatment period and through 150 days after the last dose of study drug. - Not to donate or freeze sperm during the course of this study or within 150 days after receiving their last dose of study drug. - Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with atezolizumab and durvalumab, female participants who are breastfeeding must agree to discontinue breastfeeding. These potential risks may also apply to iadademstat - Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants Exclusion Criteria: - Patients medicated with anti-depressants reported to have KDM1A/LSD1 inhibitory activity: Tranylcypromine or phenelzine - Patients who have not recovered from grade ≥2 adverse events (AEs) due to prior anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria. - Patients with grade ≥ 2 neuropathy will be evaluated on a case-by-case basis after consultation with the study physician - Patients who are receiving any other investigational agents or any other agent administered for the treatment of the patient's cancer within four half-lives or 4 weeks prior to cycle 1, day 1, whichever is shorter - Treatment with systemic immunostimulatory agents (including, but not limited to, interferon [IFN]-α or interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to cycle 1, day 1 - Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to cycle 1, day 1 or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: - Patients who have received acute, low dose, systemic immunosuppressant medications or one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible after Principal Investigator confirmation has been obtained. - Patients who have received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenocortical insufficiency are eligible - History of allergic reactions attributed to compounds of similar chemical or biologic composition to iadademstat, atezolizumab, or durvalumab. In particular, a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric antibodies, fusion proteins, or Chinese hamster ovary cell products or to any component of the atezolizumab formulation - Atezolizumab Concomitant Medication Considerations: Patients are not allowed to receive immunostimulatory agents, immunosuppressive medications, or herbal and natural remedies - Durvalumab Concomitant Medication Considerations: Patients are not allowed to receive immunosuppressive medications, EGFR TKIs, or herbal and natural remedies - Iadademstat Concomitant Medication Considerations: Patients are not allowed to receive prophylactic hematopoietic colony stimulating factors, any complementary or alternative medicine [any of various systems of healing or treating disease (as non-prescription drugs, herbal medicine and homeopathy)]. Use of these types of treatments must be terminated 1 week prior to start of study treatment - History of allogenic organ transplantation - Patients with active tuberculosis (TB) - Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous - History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted - Unstable angina, symptomatic or otherwise uncontrolled arrhythmia (does not include stable, lone atrial fibrillation), Fridericia's correction (QTcF) > 480 ms based on screening electrocardiogram (ECG), myocardial infarction ≤ 3 months prior to first study treatment, cerebrovascular accidents ≤ 3 months before study treatment start. Patient has congestive heart failure New York Heart Association (NYHA) class 2, 3 or 4 or patients with a history of congestive heart failure NYHA class 2, 3 or 4 in the past, unless a screening echocardiogram performed within 1 month prior to study entry demonstrates a left ventricular ejection fraction that is ≥ 45% - History or risk of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: - Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. - Patients with controlled Type 1 diabetes mellitus (HbA1c < 8%) on a stable insulin regimen may be eligible. - Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided all of the following conditions are met: - Rash must cover less than 10% of body surface area (BSA). - Disease is well controlled at baseline and only requiring low potency topical steroids. - No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids) within the previous 12 months. - Any chronic skin condition that does not require systemic therapy. - Patients without active disease in the last 5 years may be included but only after consultation with the study physician. - Patients with celiac disease controlled by diet alone - Patients should not receive vaccines 30 days prior and through 30 days after the last dose of study treatment with the exception of seasonal influenza vaccines and vaccines intended to prevent SARS-CoV-2, pneumococcal infection and coronavirus disease 2019 (COVID-19). If a patient had received a live attenuated vaccine within 30 days of the first dose of trial treatment, eligibility should be discussed with the investigator - Patient has had major surgery within 4 weeks prior to the first study dose - Patient has radiation therapy within 4 weeks prior to the first study dose excluding palliative and central nervous system (CNS) radiation - Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of iadademstat. In addition, patients with enteric stomata are also excluded - Patients with history of clinically significant bleeding, specifically any history of intracranial hemorrhage / hemorrhagic cardiovascular accident (CVA), or patients with gastrointestinal bleeding within the 3 months prior to study entry - Patients with known irreversible bleeding disorders or receiving antiplatelet therapy for other indications - Patients with uncontrolled disseminated intravascular coagulation - Patients who refuse or are unable to potentially receive blood products

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Start date: October 18, 2024

Completion date: January 31, 2026

Lead sponsor:
Agency: National Cancer Institute (NCI)
Agency class: NIH

Source: National Cancer Institute (NCI)

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06287775

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