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