Description:
This phase I trial investigates the side effects and best dose of BAY 1895344 when given
together with usual chemotherapy (irinotecan liposome or topotecan) in treating patients with
solid tumors that have spread to other places in the body (advanced), with a specific focus
on small cell lung cancer, poorly differentiated neuroendocrine cancer, and pancreatic
cancer. BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed
for cell growth. Chemotherapy drugs, such as irinotecan liposome and topotecan, work in
different ways to stop the growth of tumor cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. Adding BAY 1895344 to irinotecan
liposome or topotecan may help to slow the growth of tumors for longer than seen with those
drugs alone.
Title
- Brief Title: Testing the Addition of an Anti-cancer Drug, BAY 1895344, to Usual Chemotherapy for Advanced Stage Solid Tumors, With a Specific Focus on Patients With Small Cell Lung Cancer, Poorly Differentiated Neuroendocrine Cancer, and Pancreatic Cancer
- Official Title: BAY1895344 Plus Topoisomerase-1 (Top1) Inhibitors in Patients With Advanced Solid Tumors, Phase I Studies With Expansion Cohorts in Small Cell Lung Carcinoma (SCLC), Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) and Pancreatic Adenocarcinoma (PDA)
Clinical Trial IDs
- ORG STUDY ID:
NCI-2020-05958
- SECONDARY ID:
NCI-2020-05958
- SECONDARY ID:
10402
- SECONDARY ID:
10402
- SECONDARY ID:
UM1CA186689
- NCT ID:
NCT04514497
Conditions
- Metastatic Lung Small Cell Carcinoma
- Metastatic Malignant Solid Neoplasm
- Metastatic Neuroendocrine Carcinoma
- Metastatic Pancreatic Adenocarcinoma
- Stage III Lung Cancer AJCC v8
- Stage III Pancreatic Cancer AJCC v8
- Stage IIIA Lung Cancer AJCC v8
- Stage IIIB Lung Cancer AJCC v8
- Stage IIIC Lung Cancer AJCC v8
- Stage IV Lung Cancer AJCC v8
- Stage IV Pancreatic Cancer AJCC v8
- Stage IVA Lung Cancer AJCC v8
- Stage IVB Lung Cancer AJCC v8
- Unresectable Lung Small Cell Carcinoma
- Unresectable Malignant Solid Neoplasm
- Unresectable Neuroendocrine Carcinoma
- Unresectable Pancreatic Adenocarcinoma
Interventions
Drug | Synonyms | Arms |
---|
Elimusertib | ATR Inhibitor BAY1895344, ATR Kinase Inhibitor BAY1895344, BAY 1895344, BAY-1895344, BAY1895344 | Cohort I (BAY 1895344, irinotecan liposome) |
Irinotecan Sucrosofate | Irinotecan Liposome, MM-398, nal-IRI, Nanoliposomal Irinotecan, Nanoparticle Liposome Formulation of Irinotecan, Onivyde, PEP02 | Cohort I (BAY 1895344, irinotecan liposome) |
Topotecan Hydrochloride | Hycamptamine, Hycamtin, SKF S-104864-A, Topotecan HCl, topotecan hydrochloride (oral) | Cohort II (BAY 1895344, topotecan) |
Purpose
This phase I trial investigates the side effects and best dose of BAY 1895344 when given
together with usual chemotherapy (irinotecan liposome or topotecan) in treating patients with
solid tumors that have spread to other places in the body (advanced), with a specific focus
on small cell lung cancer, poorly differentiated neuroendocrine cancer, and pancreatic
cancer. BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed
for cell growth. Chemotherapy drugs, such as irinotecan liposome and topotecan, work in
different ways to stop the growth of tumor cells, either by killing the cells, by stopping
them from dividing, or by stopping them from spreading. Adding BAY 1895344 to irinotecan
liposome or topotecan may help to slow the growth of tumors for longer than seen with those
drugs alone.
Detailed Description
PRIMARY OBJECTIVES:
I. To assess safety and tolerability of each of the ATR kinase inhibitor BAY1895344 (BAY
1895344) plus topoisomerase 1 (top1) inhibitor (liposomal irinotecan [irinotecan liposome]
[nal-IRI] or topotecan hydrochloride [topotecan]) combinations.
II. To estimate maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of each of
the combinations.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To estimate objective response rate (ORR),
progression free survival (PFS), overall survival (OS) and duration of response (DOR) in
patients treated with each combination.
III. To estimate plasma pharmacokinetic (PK) characteristics of BAY 1895344 plus each top1
inhibitor (nal-IRI or topotecan) when used in combination.
IV. To estimate changes in pharmacodynamic (PD) markers of deoxyribonucleic acid (DNA) damage
(gamma-H2AX, pS343-NBS1) elicited by each combination from on-treatment tumor biopsies (in
dose expansion cohorts only).
EXPLORATORY OBJECTIVES:
I. To estimate response outcomes (ORR, PFS, OS, DOR) in study patients by tumor ataxia
telangiectasia mutated (ATM) expression loss (assessed by immunohistochemistry [IHC]).
II. To estimate response outcomes (ORR, PFS, OS, DOR) in study patients with tumor DNA damage
response (DDR) mutations (assessed by whole exome sequencing [WES] and ribonucleic acid [RNA]
sequencing [RNA Seq]).
OUTLINE: This is a dose-escalation study of BAY 1895344. Patients are assigned to 1 of 2
cohorts.
COHORT I: Patients receive BAY 1895344 orally (PO) twice daily (BID) on days 1 and 2 and
irinotecan liposome intravenously (IV) over 90 minutes on day 1. Cycles repeat every 14 days
in the absence of disease progression or unacceptable toxicity.
COHORT II: Patients receive topotecan IV over 30 minutes on days 1-5 and BAY 1895344 PO BID
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 for 6 months.
Trial Arms
Name | Type | Description | Interventions |
---|
Cohort I (BAY 1895344, irinotecan liposome) | Experimental | Patients receive BAY 1895344 PO BID on days 1 and 2 and irinotecan liposome IV over 90 minutes on day 1. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity. | - Elimusertib
- Irinotecan Sucrosofate
|
Cohort II (BAY 1895344, topotecan) | Experimental | Patients receive topotecan IV over 30 minutes on days 1-5 and BAY 1895344 PO BID on days 2 and 5. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. | - Elimusertib
- Topotecan Hydrochloride
|
Eligibility Criteria
Inclusion Criteria:
- DOSE ESCALATION COHORTS: Patients must have a biopsy-proven solid tumor that is
metastatic or unresectable and has progressed on at least one line of standard therapy
- DOSE EXPANSION COHORTS: Patients must have biopsy proven metastatic or unresectable
small cell lung cancer (SCLC), poorly differentiated neuroendocrine carcinoma (PD-NEC)
(any extrapulmonary neuroendocrine carcinoma with small cell or large cell histology)
or pancreatic adenocarcinoma (PDA) and have progressed on at least one line of
standard therapy
- DOSE EXPANSION COHORTS: Patients must have at least one measurable lesion outside of
the lesion to be biopsied
- Patients must be able to swallow pills
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Hemoglobin > 9 g/dL
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 2 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
- 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.
Furthermore, these patients must be asymptomatic from previously treated brain
metastases (e.g. not on steroids for neurologic symptoms within 30 days of study
enrollment)
- 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
- The effects of BAY 1895344 on the developing human fetus are unknown. For this reason
and because DNA-damage response inhibitors as well as other therapeutic agents used in
this trial are known to be teratogenic, women of child-bearing potential and men must
agree to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation and for 6
months after completion of BAY 1895344 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 6 months after completion of BAY 1895344
administration
- Patient must have the ability to understand and the willingness to sign a written
informed consent document. Participants with impaired decision-making capacity (IDMC)
who have a legally-authorized representative (LAR) and/or family member available will
also be eligible
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study
- Patients 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
- Patients who are receiving any other investigational agents
- The investigator(s) must state a medical or scientific reason if patients who have
brain metastases will be excluded from the study
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BAY 1895334 or other agents used in study
- Patients receiving any medications or substances that are substrates of CYP3A4 with a
narrow therapeutic window, or strong inhibitors/inducers of CYP3A4 are ineligible, if
they cannot be transferred to alternative medication. 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 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
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because BAY 1895344 is agent with 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 BAY 18953354, breastfeeding should be discontinued if the mother is
treated with BAY 18953354. These potential risks may also apply to other agents used
in this study
- Patients with an uncontrolled infection requiring IV antibiotics will not be eligible
to participate in the study
- Patients who have previously been treated with any of the study compounds will not be
eligible to participate in the study
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum tolerated dose (MTD) (Dose Escalation Phase) |
Time Frame: | Up to 21 days |
Safety Issue: | |
Description: | Defined by occurrence of >= 2 dose limiting toxicities (DLTs) defined as grade 4 neutropenia lasting >= 7 days, grade 4 thrombocytopenia, grade 4 anemia, grade 3 neutropenia with fever, grade 3 thrombocytopenia with bleeding, any grade 3 hematologic toxicity lasting >= 7 days (counting from first day of toxicity grade recognition) or any non-hematologic grade >= 2 adverse events (AEs) lasting >= 7 days (with the exception of grade 2 [G2] fatigue, G2 nausea or G2 diarrhea) (counting from first day of toxicity grade recognition) in any dose level during cycle 1 (C1) of treatment. DLTs will be graded by Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. |
Secondary Outcome Measures
Measure: | Objective response rate (ORR) |
Time Frame: | Up to 12 weeks |
Safety Issue: | |
Description: | Will be estimated by measuring the number of patients who achieve complete response or partial response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on 12-week restaging computed tomography (CT) scans from the total number of patients who received the study treatment. |
Measure: | Duration of response (DOR) |
Time Frame: | From when a patient achieves disease control (complete response, partial response, stable disease) on a restaging scan to the time of radiographic progression, assessed up to 6 months post-treatment |
Safety Issue: | |
Description: | DOR will be estimated by the Kaplan-Meier method. |
Measure: | Progression-free survival (PFS) |
Time Frame: | From when a patient starts treatment to when they demonstrate radiographic progression or succumb to the disease, assessed up to 6 months post-treatment |
Safety Issue: | |
Description: | PFS will be estimated by the Kaplan-Meier method. |
Measure: | Overall survival (OS) |
Time Frame: | From when a patient starts treatment to the date they succumb to the disease, assessed up to 6 months post-treatment |
Safety Issue: | |
Description: | OS will be estimated by the Kaplan-Meier method. |
Measure: | Maximum concentration (Cmax) |
Time Frame: | Cycle 1, days 1, 2, 3, and 4 |
Safety Issue: | |
Description: | Will be estimated for each study drug based upon plasma collections from cycle 1 in all study patients. |
Measure: | Area under the concentration-time curve (AUC) |
Time Frame: | Cycle 1, days 1, 2, 3, and 4 |
Safety Issue: | |
Description: | Will be estimated for each study drug based upon plasma collections from cycle 1 in all study patients. |
Measure: | Changes in tumor expression patterns of gamma-H2AX |
Time Frame: | Baseline up to cycle 1, day 6 |
Safety Issue: | |
Description: | Will be estimated for expansion cohort only study patients. |
Measure: | Changes in tumor expression patterns of pS343-NBS1 |
Time Frame: | Baseline up to cycle 1, day 6 |
Safety Issue: | |
Description: | Will be estimated for expansion cohort only study patients. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Last Updated
February 11, 2021