Clinical Trials /

Testing the Addition of an Anti-cancer Drug, Adavosertib, to Radiation Therapy for Patients With Incurable Esophageal and Gastroesophageal Junction Cancers

NCT04460937

Description:

This phase I trial investigates the side effects and best dose of adavosertib and how well it works when given in combination with radiation therapy in treating patients with esophageal or gastroesophageal junction cancer for which no treatment is currently available (incurable). Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving adavosertib together with radiation therapy kill more tumor cells than radiation therapy alone in treating patients with esophageal and gastroesophageal junction cancer.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Esophageal Adenocarcinoma
  • Esophageal Adenosquamous Carcinoma
  • Esophageal Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, Adavosertib, to Radiation Therapy for Patients With Incurable Esophageal and Gastroesophageal Junction Cancers
  • Official Title: A Phase 1 Trial Combining WEE1 Inhibitor Adavosertib (AZD1775) With Radiation Therapy for Metastatic or Inoperable and Ineligible for Definitive Chemoradiation Esophageal and Gastroesophageal Junction Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-04698
  • SECONDARY ID: NCI-2020-04698
  • SECONDARY ID: 10389
  • SECONDARY ID: 10389
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT04460937

Conditions

  • Clinical Stage III Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage III Esophageal Squamous Cell Carcinoma AJCC v8
  • Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IV Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IV Esophageal Squamous Cell Carcinoma AJCC v8
  • Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVA Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
  • Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IVB Esophageal Adenocarcinoma AJCC v8
  • Clinical Stage IVB Esophageal Squamous Cell Carcinoma AJCC v8
  • Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Distal Esophagus Adenocarcinoma
  • Gastric Cardia Adenocarcinoma
  • Metastatic Esophageal Adenocarcinoma
  • Metastatic Esophageal Squamous Cell Carcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Metastatic Malignant Neoplasm in the Brain
  • Metastatic Malignant Neoplasm in the Leptomeninges
  • Pathologic Stage III Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage III Esophageal Squamous Cell Carcinoma AJCC v8
  • Pathologic Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8
  • Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8
  • Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IV Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IV Esophageal Squamous Cell Carcinoma AJCC v8
  • Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVA Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
  • Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Pathologic Stage IVB Esophageal Adenocarcinoma AJCC v8
  • Pathologic Stage IVB Esophageal Squamous Cell Carcinoma AJCC v8
  • Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage III Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage III Esophageal Squamous Cell Carcinoma AJCC v8
  • Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIA Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIA Esophageal Squamous Cell Carcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIB Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIB Esophageal Squamous Cell Carcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IV Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IV Esophageal Squamous Cell Carcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVA Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVA Esophageal Squamous Cell Carcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVB Esophageal Adenocarcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVB Esophageal Squamous Cell Carcinoma AJCC v8
  • Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Unresectable Esophageal Adenocarcinoma
  • Unresectable Esophageal Carcinoma
  • Unresectable Esophageal Squamous Cell Carcinoma
  • Unresectable Gastroesophageal Junction Adenocarcinoma

Interventions

DrugSynonymsArms
AdavosertibAZD-1775, AZD1775, MK-1775, MK1775Treatment (radiation therapy, adavosertib)

Purpose

This phase I trial investigates the side effects and best dose of adavosertib and how well it works when given in combination with radiation therapy in treating patients with esophageal or gastroesophageal junction cancer for which no treatment is currently available (incurable). Adavosertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving adavosertib together with radiation therapy kill more tumor cells than radiation therapy alone in treating patients with esophageal and gastroesophageal junction cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To identify the maximally tolerated dose of adavosertib (AZD1775) to be used in
      combination with radiation therapy for patients with esophageal/gastroesophageal junction
      (GEJ) cancer that is metastatic or inoperable and not eligible for definitive chemoradiation.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. To evaluate the efficacy of AZD1775 when
      administered in combination with radiation therapy by assessing changes in Ogilvie dysphagia
      score following treatment, time to second intervention for dysphagia, and overall survival.

      III. To identify biomarkers that are predictive for response to experimental therapy.

      OUTLINE: This is a dose escalation study of adavosertib.

      Patients undergo radiation therapy once daily (QD) 5 days per week for 3 weeks in the absence
      of disease progression or unacceptable toxicity. Patients also receive adavosertib orally
      (PO) QD for 2-5 days (depending on dose level) during weeks 1 and 3 of radiation therapy in
      the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 3 weeks, every 3 months for
      2 years, then every 6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (radiation therapy, adavosertib)ExperimentalPatients undergo radiation therapy QD 5 days per week for 3 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive adavosertib PO QD for 2-5 days (depending on dose level) during weeks 1 and 3 of radiation therapy in the absence of disease progression or unacceptable toxicity.
  • Adavosertib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed esophageal cancer (either squamous cell or
             adenocarcinoma), including Siewert gastroesophageal junction adenocarcinomas types 1
             and 2, that is inoperable and not eligible for definitive chemoradiation after
             multidisciplinary review or have pathologically confirmed or imaging consistent with
             metastatic disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Karnofsky >= 70%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Hemoglobin >= 9 g/dL

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 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

          -  Creatinine =< 1.5 x 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

          -  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 new or progressive brain metastases (active brain metastases) or
             leptomeningeal disease are eligible if the treating physician determines that
             immediate CNS specific treatment is not required and is unlikely to be required during
             the first cycle of therapy

          -  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

          -  Patients able to swallow whole capsules. Patients with esophageal stents and/or
             feeding tubes are eligible but must be able to swallow whole capsules. Capsules may
             not be opened or put down a feeding tube

          -  Patients with a life expectancy > 3 months

          -  Patients must have an electrocardiogram (ECG) within 8 weeks prior to treatment
             assignment and must have no clinically important abnormalities in rhythm, conduction
             or morphology of resting ECG

               -  Resting corrected QTc interval using the Fridericia formula (QTcF) > 480 msec (as
                  calculated per institutional standards) obtained from an ECG (Note: if one ECG
                  demonstrates a QTcF > 480 msec, then a mean QTcF of =< 480 msec obtained from 3
                  ECGs 2-5 minutes apart, is required at study entry)

               -  Patients with congenital long QT syndrome are excluded

          -  The effects of AZD1775 on the developing human fetus are unknown. For this reason and
             because 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) for 2 weeks prior to study drug exposure,
             the duration of study participation, and for 1 month after completing treatment. Women
             of child-bearing potential must have a negative serum or urine pregnancy test (minimum
             sensitivity 25 IU/L or equivalent units of HCG) within 1 week of registration. 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 for
             the duration of study participation and for 3 months after completion of treatment.
             Male patients should not donate sperm during exposure to study drug and for 3 months
             after study drug discontinuation

          -  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 3 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

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to AZD1775

          -  Patients receiving any medications or substances that are strong inhibitors or
             inducers of CYP3A4 are ineligible. 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 AZD1775 is a WEE1 inhibiting 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 AZD1775, breastfeeding should be discontinued if the
             mother is treated with AZD1775. These potential risks may also apply to other agents
             used in this study

          -  Prior thoracic or abdominal radiation therapy for cancer

          -  Patients with congenital long QT syndrome or with a history of Torsades de pointes
             unless all risk factors contributed to Torsades have been corrected. AZD1775 has not
             been studied in patients with ventricular arrhythmias or recent myocardial infarction

          -  Eligibility of subjects receiving any medications or substances with the potential to
             affect the activity or pharmacokinetics of AZD1775 will be determined following review
             by the principal investigator

          -  Human immunodeficiency virus (HIV) positive patients on antiretroviral therapy are
             ineligible because of the potential for pharmacokinetic (PK) interactions. Components
             of highly active antiretroviral therapy (HAART) therapy are inhibitors of CYP3A4 which
             should be avoided
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:After completion of treatment
Safety Issue:
Description:Will employ a BOIN design where the target toxicity rate for the MTD is 25% with 75% dose-elimination cut-off.

Secondary Outcome Measures

Measure:Symptom relief rate
Time Frame:After completion of treatment
Safety Issue:
Description:Will be calculated with 95% binomial confidence intervals.
Measure:Time to second intervention for dysphagia
Time Frame:The time from initiation of therapy to the time of second intervention for dysphagia, assessed up to 5 years
Safety Issue:
Description:Patient dysphagia will be evaluated using the Ogilvie dysphagia score, comparing pre-treatment to post-treatment scores
Measure:Overall survival
Time Frame:From date of patient enrollment to death due to any cause, assessed up to 5 years after completion of treatment
Safety Issue:
Description:Survival will initially be analyzed using Kaplan-Meier methods, resulting in median survival times with 95% confidence interval (CI).
Measure:Ogilvie dysphagia scores
Time Frame:At baseline and after completion of treatment
Safety Issue:
Description:The scores will be summarized and compared using paired t-test or Wilcoxon signed-rank test. Patient dysphagia will be evaluated using the Ogilvie dysphagia score, comparing pre-treatment to post-treatment scores.
Measure:Biomarkers
Time Frame:Up to 5 years
Safety Issue:
Description:Will be described graphically or summary measures (e.g. mean and standard errors, or median and range) and compared between responders and non-responders using a two sample t-test or Wilcoxon test if the data is not normally distributed.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

June 14, 2021