Small Cell Lung CancerPhase 2NCT02688907
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
A Phase 2 study testing AZD1775 in people with Small Cell Lung Cancer, run by Samsung Medical Center at 1 site in South Korea.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Small Cell Lung Cancer
- What is being tested?
- AZD1775
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 1 siteSouth Korea
- Study dates
- 7 Jun 2016to 12 Sep 2018
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Provision of fully informed consent prior to any study specific procedures.
- Histologically confirmed SCLC with documented MYC family (MYC, MYCN, MYCL) amplification or CDKN2A mutation combined with TP53 mutation.
- Patients must be ≥20 years of age.
- 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
Show all 25Show fewer
- 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.
- Previous radiotherapy is allowed.
- Provision of tumor sample (from either archival or fresh biopsy)
- Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
- ECOG performance status 0-2
- Patients must have a life expectancy ≥ 3 months from proposed first dose date.
- 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)
- At least one measurable lesion that can be accurately assessed by imaging or physical examination at baseline and follow up visits.
- Negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1, if woman of childbearing potential
- 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.
- 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
Who cannot join
- More than two prior chemotherapy regimen for the treatment of small cell lung cancer
- Any previous treatment with P53 inhibitors (small molecules)
- 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.
- Patients unable to swallow orally administered medication.
- 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).
- 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.
Show all 15Show fewer
- 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.
- With the exception of alopecia, any ongoing toxicities (>CTCAE grade 1) caused by previous cancer therapy.
- Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks before the enrollment.
- 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.
- 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).
- Female patients who are breast-feeding or child-bearing
- 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
- Major surgical procedures ≤28 days of beginning study treatment, or minor surgical procedures ≤7 days
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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).
Read more
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.
Read the 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.
- Conditions
- Small Cell Lung Cancer
- Being tested
- AZD1775
- Medical subject headings
- Small Cell Lung Carcinoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AZD1775Drug
Dosage and Schedule : AZD1775 175 mg BID per os every 12 hours (x 6 doses, 3 days) administered days 1-3 the first \& second weeks every 21 days Patients will continue to receive study treatment as described above, until they demonstrate objective disease progression (determined by RECIST 1.1) or they meet any other discontinuation criteria.
| Study group | Role | What they receive |
|---|---|---|
| AZD1775 | Experimental | AZD1775 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. Receives: Drug: AZD1775 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective response rate (ORR) by RECIST 1.1
Measured: 24 months
Secondary outcomes (5)
Duration of response
Measured: 24 months
Disease control rate
Measured: 8 weeks
Overall survival (OS) by Kaplan-Meier method
Measured: 24 months
Progression-free survival (PFS) calculated by Kaplan-Meier method
Measured: 24 months
Number of subjects with Adverse Events as a measure of safety
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2016 (estimated)
- Study start7 Jun 2016
- Primary completion27 Dec 2017
- Study completion12 Sep 2018
Why it stopped: change regimen
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by Samsung Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- Samsung Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Keunchil Park, Samsung Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02688907
- Sponsor's protocol ID
- 2016-02-073
- Status last verified
- Sep 2018
- First submitted
- 18 Feb 2016
- Last updated
- 20 Sep 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02688907
- Acronym / sponsor ID
- 2016-02-073
- Conditions
- Small Cell Lung Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: change regimen
- Enrolment
- 7 participants (actual)
- Lead sponsor
- Samsung Medical CenterUniversity, hospital or other
- Study start
- 7 Jun 2016 (actual)
- Primary completion
- 27 Dec 2017 (actual)
- Study completion
- 12 Sep 2018 (actual)
- First posted
- 23 Feb 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| AZD1775 | Experimental | Drug: AZD1775AZD1775 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. |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (25 listed)
- Provision of fully informed consent prior to any study specific procedures.
- Histologically confirmed SCLC with documented MYC family (MYC, MYCN, MYCL) amplification or CDKN2A mutation combined with TP53 mutation.
- Patients must be ≥20 years of age.
- Small cell lung cancer that has progressed during or after first-line therapy.
- Previous radiotherapy is allowed.
Key exclusion criteria (15 listed)
- More than two prior chemotherapy regimen for the treatment of small cell lung cancer
- Any previous treatment with P53 inhibitors (small molecules)
- 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.
- Patients unable to swallow orally administered medication.
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AZD1775Dosage and Schedule : AZD1775 175 mg BID per os every 12 hours (x 6 doses, 3 days) administered days 1-3 the first \& second weeks every 21 days Patients will continue to receive study treatment as described above, until they demonstrate objective disease progression (determined by RECIST 1.1) or they meet any other discontinuation criteria. | Drug | AZD1775 |
Primary outcome
Objective response rate (ORR) by RECIST 1.1
Time frame: 24 months
5 secondary outcomes
Duration of response
Time frame: 24 months
Disease control rate
Time frame: 8 weeks
Overall survival (OS) by Kaplan-Meier method
Time frame: 24 months
Progression-free survival (PFS) calculated by Kaplan-Meier method
Time frame: 24 months
Number of subjects with Adverse Events as a measure of safety
Time frame: 24 months
Results and safety
The study was stopped early (reason given: change regimen). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Sep 2018.
Related trials for Small Cell Lung Cancer
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingObservational study
A Prospective ,Multicenter ,Non-interventional ,Real-world Study Observing Changes in Molecular Markers Osimertinib Targeted Therapy in EGFRm NSCLC
Non Small Cell Lung Cancer
RecruitingPhase 3
A Study Evaluating Sotorasib Platinum Doublet Combination Versus Pembrolizumab Platinum Doublet Combination as a Front-Line Therapy in Participants With Stage IV or Advanced Stage IIIB/C Nonsquamous Non-Small Cell Lung Cancers (CodeBreaK 202)
Non-Small Cell Lung Cancer (NSCLC)
RecruitingPhase 2
A UGT1A1 Genotype-Directed Study of Belinostat Pharmacokinetics and Toxicity
Carcinoma, Neuroendocrine, Tumor, Neuroendocrine
Active, not recruitingPhase 2
Datopotamab Deruxtecan (Dato-DXd, DS-1062a) in Advanced and/or Unresectable Non-Small Cell Lung Cancer
Metastatic Lung Cancer, Advanced Non Small Cell Lung Cancer
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing AZD1775 in people with Small Cell Lung Cancer, run by Samsung Medical Center at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 25 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 20 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: change regimen). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective response rate (ORR) by RECIST 1.1 (time frame: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Sep 2018.