Clinical Trials /

Trial of ZN-A-1041 Enteric Capsules in Patients With HER2-Positive Advanced Solid Tumors

NCT04487236

Description:

This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination with Capecitabine in patients with HER2-positive advanced solid tumors with or without brain metastases. The study will consist of three phases: phase 1a (dose escalation with ZN-A-1041 monotherapy), phase 1b (dose escalation with ZN-A-1041 and Capecitabine combination therapy) and phase 1c (dose expansion with ZN-A-1041 and Capecitabine combination therapy).

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trial of ZN-A-1041 Enteric Capsules in Patients With HER2-Positive Advanced Solid Tumors
  • Official Title: A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of ZN-A-1041 Enteric Capsules as a Single Agent or in Combination With Capecitabine Tablets in Patients With HER2-Positive Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: ZN-A-1041-101
  • NCT ID: NCT04487236

Conditions

  • Advanced Solid Tumors
  • HER2-positive Breast Cancer

Interventions

DrugSynonymsArms
ZN-A-1041 50mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 50mg
ZN-A-1041 100mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 100mg
ZN-A-1041 200mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 200mg
ZN-A-1041 400mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 400mg
ZN-A-1041 600mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 600mg
ZN-A-1041 800mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 800mg
ZN-A-1041 1000mg BIDZN-A-1041 Enteric CapsulesZN-A-1041 1000mg
ZN-A-1041 Level 1 +CapecitabineZN-A-1041 Enteric CapsulesZN-A-1041 level 1+Capecitabine 1000 mg/m2
ZN-A-1041 Level 2 +CapecitabineZN-A-1041 Enteric CapsulesZN-A-1041 level 2+Capecitabine 1000 mg/m2
ZN-A-1041 Level 3 +CapecitabineZN-A-1041 Enteric CapsulesZN-A-1041 level 3 +Capecitabine

Purpose

This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination with Capecitabine in patients with HER2-positive advanced solid tumors with or without brain metastases. The study will consist of three phases: phase 1a (dose escalation with ZN-A-1041 monotherapy), phase 1b (dose escalation with ZN-A-1041 and Capecitabine combination therapy) and phase 1c (dose expansion with ZN-A-1041 and Capecitabine combination therapy).

Detailed Description

      Phase 1a of the study will adopt the "modified 3+3" dose escalation design with a total of 7
      planned dose levels. Patients with HER2-positive advanced solid tumor (including those with
      brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041
      followed by multiple-dose administration of ZN-A-1041.Phase 1b of the study will adopt the
      "traditional 3+3" dose escalation design with a total of 2 planned dose levels. The dose
      levels will be determined based on the MTD identified in the phase 1a study.

      In phase 1b, patients with HER2-positive advanced breast cancer (including those with brain
      metastases) will be enrolled to receive multiple doses of ZN-A-1041 in combination with
      Capecitabine. Patients with HER2-positive breast cancer with brain metastases were planned to
      be enrolled in the Phase 1c of the study to receive ZN-A-1041 in combination with
      Capecitabine. The dose levels will be determined based on the recommended doses obtained from
      the Phase 1b study.

      Each phase of the study includes a screening period, a treatment period and a follow-up
      period. During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as
      monotherapy and in combination with Capecitabine in the subjects will be collected and
      analyzed, thereby providing RP2D for the subsequent clinical trials.
    

Trial Arms

NameTypeDescriptionInterventions
ZN-A-1041 50mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle
  • ZN-A-1041 50mg BID
ZN-A-1041 100mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle
  • ZN-A-1041 100mg BID
ZN-A-1041 200mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle
  • ZN-A-1041 200mg BID
ZN-A-1041 400mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle
  • ZN-A-1041 400mg BID
ZN-A-1041 600mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle
  • ZN-A-1041 600mg BID
ZN-A-1041 800mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle
  • ZN-A-1041 800mg BID
ZN-A-1041 1000mgExperimentalPhase 1a: Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle
  • ZN-A-1041 1000mg BID
ZN-A-1041 level 1+Capecitabine 1000 mg/m2ExperimentalPhase 1b: ZN-A-1041 level 1+Capecitabine 1000 mg/m2; ZN-A-1041 Level 1 (The previous dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study. Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.
  • ZN-A-1041 Level 1 +Capecitabine
ZN-A-1041 level 2+Capecitabine 1000 mg/m2ExperimentalPhase 1b: ZN-A-1041 level 2+Capecitabine 1000 mg/m2; ZN-A-1041 Level 2 ( dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study. Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.
  • ZN-A-1041 Level 2 +Capecitabine
ZN-A-1041 level 3 +CapecitabineExperimentalPhase 1c: The actual dose levels of ZN-A-1041 to be used in the combination Capecitabine will be determined based on the MTD identified in the Phase 1b study.
  • ZN-A-1041 Level 3 +Capecitabine

Eligibility Criteria

        Key inclusion criteria:

          1. Ages Eligible for Study: 18 Years and older

          2. Sexes Eligible for Study: All

          3. ECOG performance status of 0 to 1

          4. Patients are defined as follows:

             a) Phase 1a study will enroll patients with HER2-positive advanced solid tumor ; Phase
             1b study will enroll patients with HER2-positive advanced breast cancer.

             i.HER2-positive is defined as Immunohistochemistry (IHC) (++) and Fluorescence In Situ
             Hybridization (FISH) positive, or IHC (+++).

             ii.For patients who have no brain metastases, the following criteria should be met:
             (1) Patients should be relapsed or refractory to existing therapy(ies) known to
             provide clinical benefit for the underlying cancer or have been intolerant of such
             therapies (2) Have at least one extracranial measurable lesion per RECIST v1. 1 iii.
             For patients with brain metastasis, the following criteria should be met: (1) Have
             received prior treatment or declined the above treatment according to the protocol
             requirements; (2) Patients with HER2-positive gastric cancer must have previously
             received Trastuzumab (3) Do not require immediate local treatment during the trial
             period according to the protocol requirements.

             iv. For patients who have received previous tyrosine kinase inhibitor (TKI) treatment
             or chemotherapy, the interval between the last treatment and the first administration
             of the study drug in this trial should be at least 3 weeks. For patients who receive
             antibody or antibody-drug conjugate (ADC), the interval between the last treatment and
             the first administration of the study drug in this trial should be at least 4 weeks.

             b) Phase 1c study will enroll patients with HER2-positive breast cancer with brain
             metastases:

             i. HER2 positive is defined as IHC (++) and FISH positive, or IHC (+++);

             ii. Patients do not require immediate local treatment during the trial period
             according to the protocol requirements.

             iii. Patients should have at least one measurable intracranial lesion accurately
             measured at baseline by magnetic resonance imaging (MRI).

          5. Life expectancy ≥6 months;

          6. Have adequate organ and bone marrow function within 7 days before the first
             administration according to the protocol

          7. Man of reproductive potential or women of child-bearing potential shall be use of
             highly effective methods of birth control (such as oral contraceptives, intrauterine
             contraceptive device, abstinence or barrier contraception in combination with
             spermicide) during the trial, and continue to practice contraception for 3 months
             after the last administration.

          8. Subject or legally authorized representative of a subject must provide signed informed
             consent document, have good compliance, and are cooperative with the follow-ups.

        Key exclusion criteria:

          1. Subjects who have participated in any clinical study or received any clinical study
             drug within 4 weeks prior to the first administration;

          2. Based on screening brain MRI, any of the following criteria for patients with brain
             metastasis:

               1. progressive neurologic impairment or increased intracranial pressure

               2. any intracranial lesion thought to require immediate local therapy

               3. require antiepileptic treatment

          3. Subjects who have opportunistic infection or progressive (severe) infection

          4. Subjects who have undergone large surgeries within 4 weeks prior to the initiation of
             treatment or need large surgeries during the trials (excluding biopsy);

          5. Subjects who have intracranial hemorrhage or stroke within 6 months prior to the first
             administration;

          6. Subjects who have active gastrointestinal disorders or other diseases, which may
             significantly affect the absorption, distribution, metabolism or excretion of
             ZN-A-1041;

          7. Subjects who are currently using (or will not discontinue at least 1 week prior to the
             first administration of the trial) any drug or herbal medicine known to inhibit or
             induce CYP3A4 and CYP2C8 activity;

          8. Subjects who meet one of the following cardiac criteria:

               1. Congestive heart failure (New York Heart Association functional classification)
                  of ≥ 2

               2. Peripheral arterial disease (PAD), like Coronary artery disease, hypertrophic
                  cardiomyopathy (HCM)or Dilated cardiomyopathy

               3. Abnormalities in the ECG Measurements: such as First-degree heart block,
                  Second-degree heart block, Third-degree heart block, Prolonged PR: > 0.20s

               4. Any clinically significant supraventricular arrhythmia or ventricular arrhythmia
                  requiring treatment or intervention

               5. Angina requiring treatment

               6. Myocardial infarction within the past 12 months

               7. Percutaneous transluminal coronary angioplasty/stenting (PTCA), coronary artery
                  bypass graft (CABG) within 6 months of the first dose of the study treatment

               8. QTcF prolongation (> 470 ms for women and > 450 ms for man
                  (Fridericia-corrected)), a known history of QTcF prolongation or Torsade de
                  Pointes; or is on drugs that are required for existing medical conditions and
                  that may result in QT prolongation (e.g., anti-arrhythmic drugs)

          9. Subjects who have not fully recovered from previous treatment and still has CTCAE
             grade 1 or higher AEs, excluding alopecia. prior to the first administration;

         10. Pregnant or lactating women

         11. Subjects who are known to be allergic to ZN-A-1041 and its metabolites or its
             pharmaceutical excipients (active or not)

         12. Subjects who have serious accompanying diseases or an abnormal laboratory finding.

         13. Subjects who have serious psychological or mental abnormalities.

         14. Subjects who have complications of the central nervous system which require urgent
             neurosurgical interventions.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a
Time Frame:23days
Safety Issue:
Description:Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.

Secondary Outcome Measures

Measure:Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c
Time Frame:From baseline to Day 8
Safety Issue:
Description:To assess the AUC of ZN-A-1041 and its major metabolites;
Measure:Plasma Level of ZN-A-1041 and its major metabolites on Phase 1a,phase 1 b and 1c
Time Frame:From baseline to Day 8
Safety Issue:
Description:To assess the Cmax of ZN-A-1041 and its major metabolites;
Measure:Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c
Time Frame:From baseline to Day 8
Safety Issue:
Description:To assess the Tmax of ZN-A-1041 and its major metabolites;
Measure:The preliminary efficacy of ZN-A-1041 as a monotherapy or combination with with Capecitabine on Phase 1a,phase 1b and 1c
Time Frame:through study completion, an average of 3 year
Safety Issue:
Description:overall Response Rate (ORR);Progression free survival(PFS)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Suzhou Zanrong Pharma Limited

Trial Keywords

  • Phase 1
  • Advanced Solid Tumors
  • HER2-Positive Breast Cancer

Last Updated

July 22, 2020