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Trial of Topotecan With VX-970, an ATR Kinase Inhibitor, in Small Cell Cancers Amd Extrapulmonary Small Cell Cancers

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ClinicalTrials.gov Identifier: NCT02487095
Recruitment Status : Recruiting
First Posted : July 1, 2015
Last Update Posted : October 19, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

Background:

Chemotherapy damages cancer cell DNA so the cells die and the tumor shrinks. But it may stop working in some people over time. This is partly due to efficient DNA damage repair mechanisms used by tumor cells. VX-970 may stop cancer cells from preventing the repair of DNA damaged by chemotherapy. The purpose of this study is to see if using the chemotherapy drug topotecan along with the drug VX-970 will improve the response to chemotherapy.

Objective:

To study the safety and efficacy of VX-970 and topotecan in treating small cell lung cancer.

Eligibility:

Adults at least 18 years old with small cell lung cancer .

Design:

Participants will be screened with medical history, physical exam, blood and heart tests, and scans. Most of these tests are part of their routine care. Most of these tests will be repeated throughout the study.

The study is set in 21-day cycles. Participants will get topotecan IV on days 1 through 5. They will get VX-970 IV on day 5 alone or on day 5 and day 2.

Participants doctors will monitor them weekly for the first cycle, every 3 weeks after that.

For Part 1 of this Study the doses of topotecan and VX-970 will be increased (according to the Protocol) to determine the maximum safe dose of the combination. The maximum safe dose of the combination is the dose at which no more than 1 in 6 people have an intolerable side effect.

More participants will join in Phase 2. They will take the drugs at the maximum safe dose, on the same schedule as the drugs were taken in Phase 1.

Participants will give samples of blood, hair, and tumor tissue (optional) at different times. They will discuss side effects at every visit.

A month after stopping taking the drugs, participants will have a physical exam and blood drawn. They will have follow-up phone calls every 3 months.


Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small -Cell Lung Ovarian Neoplasms Small Cell Lung Carcinoma Uterine Cervical Neoplasms Carcinoma, Neuroendocrine Extrapulmonary Small Cell Cancer Drug: Topotecan Drug: VX-970 Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Topotecan With VX970, an ATR Kinase Inhibitor in Small Cell Cancers
Study Start Date : June 18, 2015
Estimated Primary Completion Date : May 31, 2024
Estimated Study Completion Date : October 30, 2025


Arm Intervention/treatment
Experimental: 1/Phase I
VX-970 + topotecan at escalating doses
Drug: Topotecan
Topotecan (in combination with VX-970) administered by IV Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Drug: VX-970
VX-970 (in combination with Topotecan) administered by IV Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Experimental: 2/Phase II
VX-970 + topotecan at MTD/RP2D
Drug: Topotecan
Topotecan (in combination with VX-970) administered by IV Days 1-5 in a 21 day cycle, until disease progression or development of intolerable side effects.

Drug: VX-970
VX-970 (in combination with Topotecan) administered by IV Day 5 or Days 2 and 5 in a 21 day cycle, until disease progression or development of intolerable side effects.




Primary Outcome Measures :
  1. Ph I: Maximum Tolerated Dose (MTD) of topotecan in combination with VX-970 [ Time Frame: End of Cycle 1 ]
    MTD will be determined as DLT occurring at the highest dose level

  2. Ph II: Clinical Response Rate [ Time Frame: Every two cycles ]
    Clinical response will be established at observed response rate of 20 percent (5 or more of 25 subjects having a response).



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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Both Phase I and Phase II:

    • Male and female subjects greater than or equal to 18 years of age. Because no dosing adverse event data are currently available on the use of topotecan in combination with VX-970 in subjects less than 18 years of age, children are excluded from this study, but will be eligible for future pediatrics trials.
    • ECOG performance status less than or equal to 2 (Performance Status Criteria)
    • Patients must have measurable disease, per RECIST 1.1. Subjects with evaluable, but not measurable disease will be eligible for Phase 1.
    • Subjects must not have received chemotherapy, or undergone major surgery within 4 weeks and radiotherapy within 24 hours prior to enrollment.
    • Adequate organ functions

      • Hemoglobin greater than or equal to 9.0 g/dL
      • Absolute neutrophil count greater than or equal to 1.5x10^9/L
      • Platelets greater than or equal to 100x10^9/L
      • Total Bilirubin less than or equal to 2.0 mg/dL
      • Transaminases less than or equal to 2 x ULN or if liver metastases were present, less than or equal to 3xULN
      • Creatinine less than or equal to 1.5 mg/dL or creatinine clearance by Cockcroft-Gault formula greater than or equal to 60 mL/min
    • Ability of subject to understand and the willingness to sign a written informed consent document.
    • The effects of VX-970 on the developing human fetus are unknown For this reason and because topotecan is 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, during study participation and for 6

months after the last dose study therapy. 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.

  • Phase I:

    • Subjects with histologically confirmed SCLC, NSCLC, ovarian cancer, cervical cancer, and neuroendocrine cancers will be eligible. Pathological confirmation of diagnosis will be done at NCI Laboratory of Pathology. Patients with other histologies will be allowed if no standard treatment options exist.
    • At least one prior chemotherapy
    • NSCLC subjects with EGFR mutations or ALK translocations should have previously received appropriate FDA approved therapies in addition to prior chemotherapy
  • Phase II:

    • Histological confirmation of SCLC, or extrapulmonary small cell cancer. Although NCI confirmation of pathology is not required prior to starting treatment, every effort will be made to obtain outside pathology to be reviewed by an NCI pathologist.

EXCLUSION CRITERIA:

  • Subjects with tumor amenable to potentially curative therapy.
  • Subjects who are receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to (study agent) or other agents used in study.
  • Subjects with symptomatic brain metastases will be excluded from trial secondary to poor prognosis. However, subjects who have had treatment for their brain metastasis and whose brain disease is stable without steroid therapy for 1 week or on physiologic doses of steroids may be enrolled.
  • Subjects requiring any medications or substances that are strong inhibitors or inducers of CYP3A during the course of the study are ineligible. Lists including strong inhibitors and inducers of CYP 3A4 are provided.
  • Subjects with evidence of severe or uncontrolled systemic disease, or any concurrent condition, which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, stroke/cerebrovascular accident within the past 6 months, or psychiatric illness/social situations which would jeopardize compliance with the protocol.
  • HIV-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with VX-970. In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy.
  • Pregnant women are excluded from this study because topotecan is a Class D agent with the potential for teratogenic or abortifacient effects and because the effects of VX- 970 on the developing human fetus are currently unknown. In addition, because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with topotecan or VX-970, breastfeeding should be discontinued if the mother is treated with these agents.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02487095


Contacts
Contact: Linda C Sciuto, R.N. (240) 760-6117 lsciuto@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Anish Thomas, M.D. National Cancer Institute (NCI)

Additional Information:
Publications:
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02487095     History of Changes
Other Study ID Numbers: 150150
15-C-0150
First Posted: July 1, 2015    Key Record Dates
Last Update Posted: October 19, 2018
Last Verified: August 31, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
RB1 Inactivation
Kinase Inhibitor
DNA Damage Response Network
MYC And CCNE1 Activation
Defective ATM-p53 Signaling Pathway

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Ovarian Neoplasms
Small Cell Lung Carcinoma
Uterine Cervical Neoplasms
Carcinoma, Small Cell
Carcinoma, Neuroendocrine
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Uterine Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Neuroendocrine Tumors