This phase II trial studies how well M6620 works when given in combination with topotecan
hydrochloride (topotecan) compared with topotecan alone in treating patients with small cell
lung cancer that has come back (relapsed), or small cell cancer that arises from a site other
than the lung (extrapulmonary). Drugs used in chemotherapy, such as topotecan hydrochloride,
work by damaging the DNA (deoxyribonucleic acid) in tumor cells, causing those cells to die
and the tumor to shrink. However, some tumor cells can become less affected by chemotherapy
because they have ways to repair the damaged DNA. The addition of M6620 could help topotecan
hydrochloride shrink the cancer and prevent it from returning by blocking enzymes needed for
DNA repair.
PRIMARY OBJECTIVE:
I. To determine if the combination of M6620 with topotecan hydrochloride (topotecan) will
result in an improvement in progression-free survival (PFS) compared to topotecan alone in
patients with relapsed small cell lung cancer (SCLC).
SECONDARY OBJECTIVE:
I. To determine the objective response rate (ORR) and overall survival (OS) with the
combination of M6220 and topotecan in patients with relapsed SCLC and extrapulmonary small
cell cancers.
EXPLORATORY OBJECTIVES:
I. To perform molecular profiling assays on malignant and normal tissues, including, but not
limited to ribonucleic acid (RNA) sequencing (RNA-Seq):
Ia. To assess expression of genes Schlafen family member 11 (SLFN11), MYC, and
ataxia-telangiesctasia mutated (ATM) among others.
Ib. To identify potential predictive biomarkers of response to a combination of M6620 with
topotecan.
Ic. Identify mechanisms of drug sensitivity and resistance using deoxyribonucleic acid (DNA)-
and RNA-based assessment platforms.
II. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
and future research; specimens will be annotated with key clinical data, including
presentation, diagnosis, staging, summary treatment, and if possible, outcome.
III. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA
analysis), and nucleic acids obtained from patients at the Experimental Therapeutics Clinical
Trial Network (ETCTN) Biorepository at Nationwide Children's Hospital.
IV. To characterize circulating cell-free DNA (cfDNA) and circulating tumor cells in patients
with relapsed SCLC and extrapulmonary small cell cancers.
V. To identify potential predictive biomarkers of response to a combination of M6620 with
topotecan in patients with extrapulmonary small cell cancers.
OUTLINE: Patients are randomized to 1 of 2 arms. Patients with extrapulmonary small cell
cancer are assigned to Arm II while patients with relapsed small cell lung cancer are
assigned to both arms.
ARM I: Patients receive topotecan hydrochloride intravenously (IV) over 30 minutes on days
1-5. Cycles repeat every 21 days in the absence of disease progression or unacceptable
toxicity. Patients may crossover to Arm II at disease progression.
ARM II: Patients receive topotecan hydrochloride IV over 30 minutes on days 1-5 and M6620 IV
over 60 minutes on days 2 and 5. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 4 weeks and then every 12
weeks thereafter.
Inclusion Criteria:
- Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC
at diagnosis, with relapse at study entry with measurable disease at random assignment
per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Both platinum-sensitive
and platinum-resistant patients will be included
- Patients with extrapulmonary small cell cancers (cancers with small cell morphology
and arising outside the lung, such as small cell prostate, bladder, etc) will be
eligible for the exploratory cohort
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Hemoglobin >= 9.0 g/dL - patients may receive transfusion to meet the hemoglobin (Hb)
eligibility
- Absolute neutrophil count (ANC) >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 2 mg/dL
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 x institutional upper limit of normal (ULN)
- Creatinine =< institutional ULN OR
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 unless data exists supporting
safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral
therapy are eligible as long as they are on effective anti-retroviral therapy with
undetectable viral load within 6 months and there is no drug-drug interaction with
M6220
- 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
- The effects of M6620 on the developing human fetus are unknown. For this reason and
because DNA-damage response (DDR) inhibitors as well as other therapeutic agents used
in this trial are known to be teratogenic, women 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 6
months after completion of M6620 administration. 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. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and for 6 months after completion of M6620
administration
- Patients with treated brain metastases are eligible if they are symptomatically stable
while off steroid therapy for a minimum of 21 days
- 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
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients with symptomatic brain metastasis are not eligible due to their extremely
poor prognosis and since it is unclear whether the investigational agent penetrates
the blood-brain barrier. However, subjects who have had treatment for their brain
metastasis and are symptomatically stable while off steroid therapy for a minimum of
21 days may be enrolled
- Patients who have received prior topotecan therapy
- Patients who have had chemotherapy or radiotherapy within 3 weeks prior to enrollment
- Note: Patients who have had palliative radiotherapy may be included as long as
they have recovered from any radiotherapy related adverse events (allow at least
a week between radiotherapy completion and study treatment)
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
except hair loss and peripheral neuropathy (i.e., have residual toxicities > grade 1)
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M6620 or topotecan used in study
- M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration with
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin,
ritonavir, indinavir, nelfinavir and saquinavir) or inducers of CYP3A4 (e.g.,
rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided.
Patients requiring any medications or substances that are strong inhibitors or
inducers of CYP3A during the course of the study are ineligible. Because the lists of
these agents are constantly changing, it is important to regularly consult a
frequently-updated medical reference for a list of drugs to avoid or of which to
minimize use. The Patient Drug Interactions Handout and Wallet Card should be provided
to patients. As part of the enrollment/informed consent procedures, the patient 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 patient is considering a new
over-the-counter medicine or herbal product
- Patients with uncontrolled intercurrent illness
- Pregnant women are excluded from this study because M6620 as a DDR inhibitor may have
the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of the
mother with M6620, breastfeeding should be discontinued if the mother is treated with
M6620. These potential risks may also apply to topotecan used in this study
- Patients with high grade neuroendocrine cancers, but with no small cell morphology
will not be eligible
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Patients with Li-Fraumeni syndrome will not be eligible
