Clinical Trials /

Phase II, Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients With MYC Family Amplification or CDKN2A Mutation Combined With TP53 Mutation

NCT02688907

Description:

AZD1775 (previously known as MK-1775 in earlier studies) is an inhibitor of Wee1, a protein tyrosine kinase. Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 (CDK1) and 2 (CDK2), and is involved in regulation of the intra-S and G2 cell cycle checkpoints. CDK1 (also called cell division cycle 2, or CDC2) activity drives a cell from the G2 phase of the cell cycle into mitosis. In response to DNA damage, Wee1 inhibits CDK1 to prevent the cell from dividing until the damaged DNA is repaired (G2 checkpoint arrest). Inhibition of Wee1 is expected to release a tumor cell from chemotherapeutically-induced arrest of cell replication. In vitro experiments demonstrate that AZD1775 has synergistic cytotoxic effects when administered in combination with various DNA damaging agents that have divergent mechanisms of action. Therefore, the primary objective of the clinical development of AZD1775 is its use as a chemosensitizing drug in combination with a cytotoxic agent (or combination of agents) for treatment of advanced solid tumors. CDK2 activity drives a cell into, and through, S-phase of the cell cycle where the genome is duplicated in preparation for cell division. Inhibition of Wee1 is expected to cause aberrantly high CDK2 activity in S-phase cells which, in turn, leads to unstable DNA replication structures and ultimately DNA damage. Therefore, it is anticipated that AZD1775 will have independent anti-tumor activity in the absence of added chemotherapy. The tumor suppressor protein p53 regulates the G1 checkpoint. As the majority of human cancers harbor abnormalities in this pathway they become more dependent on S- and G2- phase checkpoints. Thus, S- and G2-checkpoint abrogation caused by inhibition of Wee1 may selectively sensitize p53-deficient cells. One hundred percent of SCLC has TP53 mutation, therefore we can expect that most of SCLC have lost G1 checkpoint and has high probability of WEE1 dependency for proper DNA repair and cell cycle progression. For this reason, SCLC could be a good clinical trial target disease for WEE1 inhibitor.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II, Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients With MYC Family Amplification or CDKN2A Mutation Combined With TP53 Mutation
  • Official Title: Phase II, Single-arm Study of AZD1775 Monotherapy in Relapsed Small Cell Lung Cancer Patients With MYC Family Amplification or CDKN2A Mutation Combined With TP53 Mutation

Clinical Trial IDs

  • ORG STUDY ID: 2016-02-073
  • NCT ID: NCT02688907

Conditions

  • Small Cell Lung Cancer

Interventions

DrugSynonymsArms
AZD1775AZD1775

Purpose

AZD1775 (previously known as MK-1775 in earlier studies) is an inhibitor of Wee1, a protein tyrosine kinase. Wee1 phosphorylates and inhibits cyclin-dependent kinases 1 (CDK1) and 2 (CDK2), and is involved in regulation of the intra-S and G2 cell cycle checkpoints. CDK1 (also called cell division cycle 2, or CDC2) activity drives a cell from the G2 phase of the cell cycle into mitosis. In response to DNA damage, Wee1 inhibits CDK1 to prevent the cell from dividing until the damaged DNA is repaired (G2 checkpoint arrest). Inhibition of Wee1 is expected to release a tumor cell from chemotherapeutically-induced arrest of cell replication. In vitro experiments demonstrate that AZD1775 has synergistic cytotoxic effects when administered in combination with various DNA damaging agents that have divergent mechanisms of action. Therefore, the primary objective of the clinical development of AZD1775 is its use as a chemosensitizing drug in combination with a cytotoxic agent (or combination of agents) for treatment of advanced solid tumors. CDK2 activity drives a cell into, and through, S-phase of the cell cycle where the genome is duplicated in preparation for cell division. Inhibition of Wee1 is expected to cause aberrantly high CDK2 activity in S-phase cells which, in turn, leads to unstable DNA replication structures and ultimately DNA damage. Therefore, it is anticipated that AZD1775 will have independent anti-tumor activity in the absence of added chemotherapy. The tumor suppressor protein p53 regulates the G1 checkpoint. As the majority of human cancers harbor abnormalities in this pathway they become more dependent on S- and G2- phase checkpoints. Thus, S- and G2-checkpoint abrogation caused by inhibition of Wee1 may selectively sensitize p53-deficient cells. One hundred percent of SCLC has TP53 mutation, therefore we can expect that most of SCLC have lost G1 checkpoint and has high probability of WEE1 dependency for proper DNA repair and cell cycle progression. For this reason, SCLC could be a good clinical trial target disease for WEE1 inhibitor.

Detailed Description

      There is only approved drug, topotecan for patients with relapsed small cell lung cancer who
      have progressed following first-line therapy. In clinical practice, topoisomerase inhibitor,
      topotecan or irinotecan is commonly used in this setting.

      AZD1775 is a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule
      inhibitor of Wee1 kinase. Wee1 is a tyrosine kinase involved in regulation of intra-S and G2
      cell cycle checkpoints through phosphorylation and inhibition of CDK2 and CDK1, respectively.
      Because activity of these and other CDKs coordinate progression through the cell cycle, they
      are inhibited at cell cycle checkpoints, causing transient arrest at the G1-, S-, and G2
      phases of the cell cycle.

      P53 is a key regulator of the G1 checkpoint and is one of the most frequently mutated genes
      in cancer. Therefore, a majority of human cancers lack G1checkpoint but retain the S- and
      G2-phase checkpoints. As a result of p53 deficiency,cells lacking the G1 checkpoint are
      predicted to be more dependent on the Wee1-mediated G2 checkpoint. Hence, p53-deficient
      tumors treated with inhibitors of Wee1 may be particularly susceptible to DNA damage because
      multiple checkpoints have been lost.

      One hundred percent of SCLC has TP53 mutation, therefore we can expect that most of SCLC have
      lost G1 checkpoint and has high probability of WEE1 dependency for proper DNA repair and cell
      cycle progression.

      Therefore, the AZD1775 monotherapy might have some clinical activity as a 2nd line therapy in
      small cell lung cancer patients.
    

Trial Arms

NameTypeDescriptionInterventions
AZD1775ExperimentalAZD1775 175 mg BID per os every 12 hours (6 doses) administered days 1-3 the first week and then days 1-3 the 2nd week of 21 day cycle.
  • AZD1775

Eligibility Criteria

        Inclusion Criteria:

          1. Provision of fully informed consent prior to any study specific procedures.

          2. Histologically confirmed SCLC with documented MYC family (MYC, MYCN, MYCL)
             amplification or CDKN2A mutation combined with TP53 mutation.

          3. Patients must be ≥20 years of age.

          4. Small cell lung cancer that has progressed during or after first-line therapy.

               -  The 1st line regimen must have contained platinum based regimen.

               -  Refractory to first-line chemotherapy or relapse within 6 months since the last
                  dose of first-line chemotherapy

               -  If the patient correspond to sensitive relapse (relapse more than 6 months since
                  the last dose of first-line chemotherapy), she/he should get second-line
                  treatment.

          5. Previous radiotherapy is allowed.

          6. Provision of tumor sample (from either archival or fresh biopsy)

          7. Patients are willing and able to comply with the protocol for the duration of the
             study including undergoing treatment and scheduled visits and examinations.

          8. ECOG performance status 0-2

          9. Patients must have a life expectancy ≥ 3 months from proposed first dose date.

         10. Patients must have acceptable bone marrow, liver and renal function measured within 14
             days prior to administration of study treatment as defined below:

               -  Haemoglobin ≥9.0 g/dL

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  White blood cells (WBC) > 3 x 109/L

               -  Platelet count ≥100 x 109/L

               -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver
                  metastases are present in which case it must be ≤ 5x ULN

               -  Serum creatinine ≤1.5 x institutional ULN and a calculated creatinine clearance
                  (CrCl) ≥45 mL/min by the Cockcroft-gault method:

             CrCl = (140-age) x (weight/kg) x (0.85 if female)

         11. At least one measurable lesion that can be accurately assessed by imaging or physical
             examination at baseline and follow up visits.

         12. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed
             prior to treatment on day 1, if woman of childbearing potential

         13. Female patients who are not of childbearing potential and fertile female patients of
             childbearing potential who agree to use adequate contraceptive measures, who are not
             breastfeeding.

         14. Fertile male patients willing to use at least one medically acceptable form of birth
             control, and must not donate sperm, for the duration of the study, and for 2 weeks
             after treatment stops

        Exclusion Criteria:

          1. More than two prior chemotherapy regimen for the treatment of small cell lung cancer

          2. Any previous treatment with P53 inhibitors (small molecules)

          3. Patients with second primary cancer, except: adequately treated non-melanoma skin
             cancer, curatively treated in-situ cancer of the cervix, or other solid tumours
             curatively treated with no evidence of disease for >2 years.

          4. Patients unable to swallow orally administered medication.

          5. Treatment with any investigational product during the last 14 days before the
             enrollment (or a longer period depending on the defined characteristics of the agents
             used).

          6. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative
             reasons), within 3 weeks from the last dose prior to study treatment (or a longer
             period depending on the defined characteristics of the agents used). The patient can
             receive a stable dose of bisphosphonates or denosumab for bone metastases, before and
             during the study as long as these were started at least 4 weeks prior to treatment.

          7. Concomitant use of known sensitive CYP3A4 substrates or CYP3A4 substrates with a
             narrow therapeutic index, or to be moderate to strong CYP3A4 inhibitor/inducer which
             cannot be discontinued to weeks prior to Day 1 of dosing and withheld throughout the
             study until 2 weeks after the last dose of study drug, Co-administration of aprepitant
             or fosaprepitant during this study is prohibitedRefer to the Section 5.9.2 and
             Appendix H for listing of all prohibited medications.

          8. With the exception of alopecia, any ongoing toxicities (>CTCAE grade 1) caused by
             previous cancer therapy.

          9. Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks
             before the enrollment.

         10. Resting ECG with measurable QTcB > 480 msec on 2 or more time points within a 24 hour
             period or family history of long QT syndrome.

         11. Patients with cardiac problem as follows: unstable angina pectoris, congestive heart
             failure, acute myocardial infarction, conduction abnormality not controlled with
             pacemaker or medication, significant ventricular or supraventricular arrhythmias
             (patients with chronic rate controlled atrial fibrillation in the absence of other
             cardiac abnormalities are eligible).

         12. Female patients who are breast-feeding or child-bearing

         13. Any evidence of severe or uncontrolled systemic disease, active infection, active
             bleeding diatheses or renal transplant, including any patient known to have human
             immunodeficiency virus (HIV), active hepatitis B or active hepatitis C

         14. Major surgical procedures ≤28 days of beginning study treatment, or minor surgical
             procedures ≤7 days

         15. Known central nervous system (CNS) disease other than neurologically stable,treated
             brain metastases - defined as metastasis having no evidence of progression or
             haemorrhage for at least 2 weeks after treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR) by RECIST 1.1
Time Frame:24 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Duration of response
Time Frame:24 months
Safety Issue:
Description:
Measure:Disease control rate
Time Frame:8 weeks
Safety Issue:
Description:
Measure:Overall survival (OS) by Kaplan-Meier method
Time Frame:24 months
Safety Issue:
Description:
Measure:Progression-free survival (PFS) calculated by Kaplan-Meier method
Time Frame:24 months
Safety Issue:
Description:
Measure:Number of subjects with Adverse Events as a measure of safety
Time Frame:24 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Samsung Medical Center

Last Updated

February 5, 2018