SUSPENDED

Testing the Combination of the Anticancer Drugs Trastuzumab Deruxtecan (DS-8201a) and Azenosertib (ZN-c3) in Patients With Stomach or Other Solid Tumors

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Conditions

Clinical Stage III Gastric Cancer AJCC v8Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8Clinical Stage IV Gastric Cancer AJCC v8Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8Locally Advanced Gastric CarcinomaLocally Advanced Gastroesophageal Junction AdenocarcinomaLocally Advanced Malignant Solid NeoplasmMetastatic Gastric CarcinomaMetastatic Gastroesophageal Junction AdenocarcinomaMetastatic Malignant Solid NeoplasmUnresectable Gastric CarcinomaUnresectable Gastroesophageal Junction AdenocarcinomaUnresectable Malignant Solid Neoplasm

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

This phase I trial tests the safety, side effects, and best dose of azenosertib in combination with trastuzumab deruxtecan in treating patients with HER2-positive and cyclin E amplified gastric or gastroesophageal junction cancer and other HER2-positive solid tumors that have spread to nearby tissue or lymph nodes (locally advanced), that have spread from where it first started (primary site) to other places in the body (metastatic), or that cannot be removed by surgery (unresectable). Azenosertib is in a class of medications called kinase inhibitors. It inhibits a protein called Wee1. Inhibition of the Wee1 protein can make tumor cells more vulnerable to chemotherapy drugs, leading to tumor cell death. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them. Giving azenosertib in combination with trastuzumab deruxtecan may be safe, tolerable, and/or more effective in treating patients with locally advanced, metastatic, or unresectable HER2-positive gastric, gastroesophageal junction, or other solid tumors, compared to just trastuzumab deruxtecan alone.

Official Title

Phase 1 Study of Trastuzumab Deruxtecan (DS-8201a) in Combination With Azenosertib (ZN-c3) in HER2-Expressing/Amplified Cyclin E-Amplified Gastric/Gastroesophageal Junction Cancer and Other Solid Tumors With HER2 Expression

Quick Facts

Study Start:2025-02-03
Study Completion:2027-07-08
Study Type:Not specified
Phase:Not Applicable
Enrollment:Not specified
Status:SUSPENDED

Study ID

NCT06364410

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years
Sexes Eligible for Study:ALL
Accepts Healthy Volunteers:No
Standard Ages:ADULT, OLDER_ADULT
Inclusion CriteriaExclusion Criteria
  1. * In the dose escalation, patients must have a histologically documented locally advanced, unresectable, or metastatic solid tumor that has progressed following at least one prior line of treatment in the metastatic setting or has no satisfactory alternative treatment option and all of the following:
  2. * HER2 expression by immunohistochemistry (IHC) (1+, 2+, or 3+) or HER2 amplification by in situ hybridization (ISH) or next generation sequencing (NGS) (on any Clinical Laboratory Improvements Amendments \[CLIA\] platform), AND
  3. * T-DXd (DS-8201a)-naive disease
  4. * In the dose expansion, patients must have histologically documented locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer that has progressed following at least one prior line of treatment in the metastatic setting and have all of the following:
  5. * CCNE1 amplification, AND
  6. * HER2 expression by IHC (1+, 2+, or 3+) or HER2 amplification by ISH or NGS (on any CLIA platform), AND
  7. * T-DXd (DS-8201a)-naive disease
  8. * Received prior trastuzumab-based treatment, if eligible for such treatment
  9. * For the dose escalation and dose expansion, patients can have evaluable or measurable disease
  10. * Potential trial participants should have recovered from clinically significant adverse events (AEs) of their most recent therapy/intervention prior to enrollment
  11. * Age ≥ 18 years. Because no dosing or AE data are currently available on the use of T-DXd (DS-8201a) in combination with azenosertib (ZN-c3) in patients \< 18 years of age, children are excluded from this study
  12. * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (Karnofsky ≥ 70%). Both T-DXd (DS-8201a) and azenosertib (ZN-c3) have fatigue as an adverse effect. Due to the overlapping adverse effect, the performance status cannot be less restrictive
  13. * Absolute neutrophil count ≥ 1.5 × 10\^9/L (within 7 days of study treatment initiation)
  14. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  15. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  16. * Hemoglobin \> 9.0 g/dL (within 7 days of study treatment initiation)
  17. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  18. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  19. * Platelets ≥ 100 × 10\^9/L (within 7 days of study treatment initiation)
  20. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  21. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  22. * Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN). Documented Gilbert syndrome is allowed if total bilirubin is ≤ 3 × institutional ULN (within 7 days of study treatment initiation)
  23. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  24. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  25. * Aspartate aminotransferase (AST \[serum glutamic-oxaloacetic transaminase (SGOT)\])/alanine aminotransferase (ALT \[serum glutamate pyruvate transaminase (SGPT)\]) ≤ 3 × institutional ULN. In the presence of liver metastases, AST or ALT up to 5 × institutional ULN is permitted (within 7 days of study treatment initiation)
  26. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  27. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  28. * Measured of calculated creatinine clearance (CrCl) ≥ 60 mL/min (CrCl should be calculated per institutional standard; glomerular filtration rate can also be used in place of CrCl) ≥ 60 mL/min for patients with creatinine levels \> 1.5 x institutional ULN (within 7 days of study treatment initiation)
  29. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  30. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  31. * International normalized ratio/prothrombin time and activated partial thromboplastin time ≤ 1.5 × institutional ULN (within 7 days of study treatment initiation)
  32. * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
  33. * No administration of granulocyte colony-stimulating factor is allowed within 1 week prior to screening assessment
  34. * Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
  35. * Human immunodeficiency virus-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  36. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  37. * 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
  38. * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
  39. * 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 study treatment
  40. * 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
  41. * Life expectancy ≥ 3 months
  42. * Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 3 days of study treatment initiation
  43. * Agents composed of HER2 antibody conjugated to a topoisomerase 1 inhibitor and azenosertib (ZN-c3) are known to be teratogenic; thus, WOCBP must agree to use highly effective contraception from time of screening and throughout the study treatment period and for at least 7 months after final study treatment 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. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period and for at least 7 months after the final study treatment administration
  44. * Women of non-childbearing potential defined as premenopausal females with documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone \> 40 mIU/mL and estradiol \< 40 pg/mL \[\< 147 pmol/L\] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for WOCBP if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their postmenopausal status, they can resume use of HRT during the study without use of a contraception method
  45. * Male patients involved with WOCBP must agree to use a highly effective form of contraception or avoid intercourse from time of screening and throughout the study treatment period and for at least 4 months after the last dose of study treatment. Male patients must not freeze or donate sperm starting at screening and throughout the study period and at least 4 months after the final study treatment administration. Preservation of sperm should be considered prior to enrollment in this study
  46. * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
  47. * Willing to undergo biopsy as required by the study (dose expansion only)
  1. * As azenosertib (ZN-c3) is a substrate of CYP3A4, use of prescription or non-prescription drugs known to be moderate or strong inhibitors or inducers of CYP3A4 are prohibited with the exception of moderate or strong inhibitors or inducers of CYP3A4 that are part of the prophylactic antiemetic regimen. Chloroquine/hydroxychloroquine are metabolized by CYP3A4 and therefore, should be prohibited. For patients who have received prior moderate or strong inhibitors or inducers of CYP3A4, the required washout period is approximately 5 half-lives prior to study treatment initiation
  2. * Patients who are receiving any other investigational agents
  3. * Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drugs
  4. * Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs)
  5. * Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e., rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy
  6. * Pregnant women are excluded from this study because T-DXd (DS-8201a) and azenosertib (ZN-c3) have the potential risk for teratogenic or abortifacient effects. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with T-DXd (DS-8201a) and azenosertib (ZN-c3), breastfeeding should be discontinued if the mother is treated with T-DXd (DS-8201a) or azenosertib (ZN-c3)
  7. * Patients with history of non-infectious pneumonitis/interstitial lung disease (ILD), current ILD, or where suspected ILD cannot be ruled out by imaging at screening
  8. * Patients with active infections requiring antibiotics at the time of study treatment initiation are not eligible
  9. * Patients with history of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills
  10. * Patients with current signs or symptoms of bowel obstruction including sub-occlusive disease related to underlying disease
  11. * Patients with a medical history of myocardial infarction within 6 months before enrollment, symptomatic congestive heart failure (New York Heart Association class IIb to IV), and/or troponin levels consistent with myocardial infarction as defined according to the manufacturer 28 days prior to enrollment
  12. * Patients with clinically significant corneal disease
  13. * Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment)
  14. * Patients with history of Torsades de Pointes unless all risk factors that contributed to Torsades de Pointes have been corrected
  15. * Based on an average of triplicate 12-lead electrocardiogram (ECG), patients with a mean resting corrected QT (QTc) interval using Fridericia formula of \> 470 msec for both males and females at screening or a history of congenital long QT syndrome will be excluded
  16. * Patients with prior treatment with a WEE1 inhibitor (dose escalation and dose expansion)
  17. * Patients with prior treatment with T-DXd (DS-8201a) or other topoisomerase inhibitors (dose escalation and dose expansion)
  18. * Patients with uncontrolled intercurrent illness
  19. * Patients with prior allogeneic organ transplantation including allogeneic stem cell transplantation
  20. * Patients with clinically significant chronic gastrointestinal disorder with diarrhea as a major symptom; ≥ grade 2 diarrhea at baseline. Please contact the protocol principal investigator (PI) for any patient with more than two episodes of diarrhea per day averaged over at least a 7-day period at time of screening to determine whether the diarrhea would be considered clinically significant
  21. * Patients with spinal cord compression

Contacts and Locations

Principal Investigator

Funda Meric-Bernstam
PRINCIPAL_INVESTIGATOR
University of Texas MD Anderson Cancer Center LAO

Study Locations (Sites)

M D Anderson Cancer Center
Houston, Texas, 77030
United States

Collaborators and Investigators

Sponsor: National Cancer Institute (NCI)

  • Funda Meric-Bernstam, PRINCIPAL_INVESTIGATOR, University of Texas MD Anderson Cancer Center LAO

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2025-02-03
Study Completion Date2027-07-08

Study Record Updates

Study Start Date2025-02-03
Study Completion Date2027-07-08

Terms related to this study

Additional Relevant MeSH Terms

  • Clinical Stage III Gastric Cancer AJCC v8
  • Clinical Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Clinical Stage IV Gastric Cancer AJCC v8
  • Clinical Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
  • Locally Advanced Gastric Carcinoma
  • Locally Advanced Gastroesophageal Junction Adenocarcinoma
  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Gastric Carcinoma
  • Metastatic Gastroesophageal Junction Adenocarcinoma
  • Metastatic Malignant Solid Neoplasm
  • Unresectable Gastric Carcinoma
  • Unresectable Gastroesophageal Junction Adenocarcinoma
  • Unresectable Malignant Solid Neoplasm