Background:
- SCLC is the most aggressive and lethal form of lung cancer. It represents 15% of all
lung cancers, with an annual incidence of over 34,000 cases in the United States alone.
- Relapsed SCLC has been traditionally classified into sensitive and resistant disease
according to the type of response to first-line therapy and to treatment-free interval.
- Topotecan is Food and Drug Administration (FDA)-approved for patients with SCLC with
chemotherapy-sensitive disease after failure of first-line chemotherapy (platinum and
etoposide).
- Topotecan inhibits re-ligation of topoisomerase I-mediated single-strand DNA breaks
leading to lethal double-strand DNA breaks (DSB).
- We showed that inhibition of ATR by short interfering RNA or VE-821 and its clinical
derivative M6620 sensitizes tumor cells to TOP1 inhibitors.
- We found that a combination of an Ataxia telangiectasia and Rad3-related (ATR) inhibitor
and topotecan can be safely combined and that heightening replicative stress in this
manner can yield durable responses in small cell cancers and initiated a Phase 1/2 trial
of the
combination.
- In this current study, we hypothesize that the combination of M6620 and topotecan can
improve progression free survival (PFS) compared with topotecan alone in patients with
relapsed SCLC.
- In the recently reported phase I clinical trial, we defined a safe and effective dose of
topotecan plus M6820. The proposed randomized phase II trial is based on promising
preliminary efficacy data seen in SCLC patients treated on phase I and the ongoing phase
II trials.
Objectives:
-To determine if the combination of M6620 with topotecan will result in an improvement in
progression-free survival (PFS) compared to topotecan alone in patients with relapsed small
cell lung cancer (SCLC).
Eligibility:
-Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC at
diagnosis, with extensive disease at study entry with measurable disease at random assignment
per RECIST 1.1. Both platinum-sensitive and platinum-resistant patients will
be included.
- Patients must be greater than or equal to18 years of age
- Patients who have received prior topotecan therapy are not eligible.
- Patients who are receiving any other investigational agents, and with uncontrolled
intercurrent illness are not eligible.
Design:
- This study is an open label, randomized phase 2 study of patients with relapsed SCLC.
- SCLC patients who have failed prior therapy will be randomized 2:1 to receive either
topotecan in combination with M6620 or topotecan alone.
- Patients will be stratified at the time of randomization for being sensitive or
resistant/refractory to prior therapy.
- Patients on the topotecan monotherapy arm will be eligible to cross-over to receive the
combination treatment at progression.
- It is expected that approximately 25-30 patients per year (about 2-3 patients per month)
can be accrued onto the randomized portion of this trial, and thus accrual will be
completed in approximately 2 years.
- A separate cohort of 20 patients with extrapulmonary small cell cancer will be accrued
while the primary cohort is accruing and will only receive the combination therapy.
- This is planned as a multicenter study through CTEP. NCI CCR will be the lead and
coordinating site
- ELIGIBILITY 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 RECIST 1.1. See Section 12 for the evaluation of measurable disease. Both
platinumsensitive 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; see Sections
2.1 and 2.2 for disease description and rationale.) will be eligible for the
exploratory cohort.
- Patients must be greater than or equal to 18 years of age because no dosing or adverse
event data are currently available on the use of M6620 in combination with topotecan
in patients <18 years of age.
- ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
60%)
- Patients must have adequate organ and marrow function as defined below:
- Hemoglobin greater than or equal to 9.0 g/dL - patients may receive transfusion
to meet the Hb eligibility.
- Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mcL
- Platelets greater than or equal to 100,000/mcL
- Total Bilirubin less than or equal to 2 mg/dL
- AST(SGOT)/ALT(SGPT) less than or equal to 3.0 (SqrRoot) institutional ULN
- Creatinine less than or equal to institutional ULN
OR
--Glomerular Filtration Rate (GFR) greater than or equal to 60 mL/min/1.73 m2 unless data
exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73m2
- 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 enrolment
- 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, HCV and
HIV protease inhibitors, nefazodone, posaconazole, telithromycin, voriconazole) 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.
