Clinical Trials /

Study of A166 in Patients With Relapsed/Refractory Cancers Expressing HER2 Antigen or Having Amplified HER2 Gene

NCT03602079

Description:

Open-label, Phase I-II, first-in-human (FIH) study for A166 monotherapy in HER2-expressing or amplified patients who progressed on or did not respond to available standard therapies. Patients must have documented HER2 expression or amplification. The patient must have exhausted available standard therapies. Patients will receive study drug as a single IV infusion. Cycles will continue until disease progression or unacceptable toxicity.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of A166 in Patients With Relapsed/Refractory Cancers Expressing HER2 Antigen or Having Amplified HER2 Gene
  • Official Title: A Phase I-II, FIH Study of A166 in Locally Advanced/Metastatic Solid Tumors Expressing Human Epidermal Growth Factor Receptor 2 (HER2) or Are HER2 Amplified That Did Not Respond or Stopped Responding to Approved Therapies

Clinical Trial IDs

  • ORG STUDY ID: KlusPharma
  • NCT ID: NCT03602079

Conditions

  • HER2-positive Breast Cancer
  • HER2 Gene Mutation
  • HER-2 Gene Amplification
  • HER2 Positive Gastric Cancer
  • Salivary Gland Cancer
  • Salivary Gland Tumor
  • Salivary Gland Carcinoma
  • Salivary Gland Neoplasms
  • Lung Cancer
  • Colo-rectal Cancer
  • Rare Diseases
  • Solid Tumor
  • Recurrent Gastric Cancer
  • Recurrent Colon Cancer
  • Recurrent Breast Cancer
  • Head and Neck Cancer
  • Head and Neck Carcinoma
  • Bladder Cancer
  • Cervical Cancer
  • Liver Cancer
  • Bile Duct Cancer
  • Urologic Cancer
  • Pancreatic Cancer
  • Prostate Cancer
  • Recurrent Prostate Cancer
  • Rectal Cancer
  • Recurrent Ovarian Carcinoma
  • Recurrent Renal Cell Cancer
  • Rectal Cancer Stage II
  • Rectal Cancer Stage I
  • Rectal Cancer Stage III
  • Skin Cancer
  • Mouth Cancer
  • Lip Cancer Stage I
  • Tongue Cancer
  • Breast Neoplasm Malignant Primary
  • Larynx Cancer
  • Tonsil Cancer
  • Palate Cancer
  • Mucoepidermoid Carcinoma
  • Primary Peritoneal Carcinoma
  • Mucinous Adenocarcinoma Gastric
  • Mucinous Breast Cancer Recurrent
  • Cholangiocarcinoma

Interventions

DrugSynonymsArms
A166Phase I: Dose Escalation

Purpose

Open-label, Phase I-II, first-in-human (FIH) study for A166 monotherapy in HER2-expressing or amplified patients who progressed on or did not respond to available standard therapies. Patients must have documented HER2 expression or amplification. The patient must have exhausted available standard therapies. Patients will receive study drug as a single IV infusion. Cycles will continue until disease progression or unacceptable toxicity.

Detailed Description

      This is an open-label, Phase I-II, first-in-human (FIH) study for A166 as monotherapy in
      HER2-expressing patients who progressed on or did not respond to available standard
      therapies. Patients enrolled in this Phase III study must have documented HER2 positivity
      defined as positive on in situ hybridization (ISH) or next-generation sequencing (NGS) or
      HER2 expression, defined as at least 1+ by validated immunohistochemistry (IHC) test. The
      patient must be, in the judgment of the investigator, an appropriate candidate for
      experimental therapy after available standard therapies have ceased to provide clinical
      benefit for their disease. Patients will receive study drug as a single IV infusion at the
      prescribed dose level in each treatment cycle. Cycles will continue until disease progression
      or unacceptable toxicity. The study is divided into 2 parts (Phase I and Phase II).
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: Dose EscalationExperimentalSix dose levels have been selected for evaluation in the Phase I part of the study: 0.3, 0.6, 1.2, 2.4, 3.6, and 4.8 mg/kg of A166
  • A166
Phase II: • Cohort 1ExperimentalHER2 positive (Immunohistochemistry (IHC) 2+ with fluorescence in situ hybridization (FISH) confirmation and Immunohistochemistry (IHC) 3+) breast cancer. Treatment with A166 at recommended Phase II dose.
  • A166
Phase II: • Cohort 2ExperimentalHER2 positive (Immunohistochemistry (IHC) 2+ with fluorescence in situ hybridization (FISH) confirmation and Immunohistochemistry (IHC) 3+) gastric cancer. Treatment with A166 at recommended Phase II dose.
  • A166
Phase II: • Cohort 3ExperimentalHER2 low expressing (Immunohistochemistry (IHC) 1+ and IHC 2+ without fluorescence in situ hybridization (FISH) confirmation) breast cancer. Treatment with A166 at recommended Phase II dose.
  • A166
Phase II: • Cohort 4ExperimentalAll cancers other than breast cancer with low HER2 expression (Immunohistochemistry (IHC) 1+ and IHC 2+ without fluorescence in situ hybridization (FISH) confirmation) and HER2 positive (IHC2+ with FISH confirmation and Immunohistochemistry (IHC) 3+) cancers other than breast and gastric cancer. Treatment with A166 at recommended Phase II dose.
  • A166

Eligibility Criteria

        Inclusion Criteria:

        Phase I

        Patients must meet the following criteria for inclusion into the study:

          1. Patients must be able to provide documented voluntary informed consent.

          2. Male or female patient ≥ 18 years.

          3. Histologically documented, incurable, locally advanced or metastatic cancer.

          4. Evaluable or measurable HER2 positive (by ISH or NGS) disease or HER2 expressing
             disease. HER2 expressing is defined in this protocol as HER2 expression of ≥ 1+
             determined by validated IHC.

          5. Patients should have no available therapy likely to convey clinical benefit.

          6. Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL.

          7. Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine
             aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN),
             with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and
             patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).

          8. Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease
             Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD)
             formulas. Note that 24 hour urine collection is not required but is allowed.

          9. ECOG Performance Status ≤ 1.

         10. Women of childbearing potential and men must agree to use an approved method of birth
             control (e.g., hormonal, barrier) while receiving study drug, and for at least 7
             months after the last dose of study drug. Women are excluded from birth control if
             they had had tubal ligation or a hysterectomy.

         11. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute
             toxicities from previous therapy, excluding alopecia and vitiligo.

        Phase II

        Patients must meet the following criteria for inclusion into the study:

          1. Patients must be able to provide documented voluntary informed consent.

          2. Male or female patient ≥ 18 years.

          3. Histologically documented, incurable, locally advanced or metastatic cancer.

          4. Evaluable or measurable HER2 positive (by ISH or NGS) disease or HER2 expressing
             disease. HER2 expressing is defined in this protocol as HER2 expression of ≥ 1+
             determined by validated IHC.

          5. Regarding previous therapy:

             5.1. Cohort 1: HER2 positive (IHC 2+ with FISH confirmation and Immunohistochemistry
             (IHC 3+) breast cancer: patients should have progressed after at least 2 previous HER2
             directed regimens in metastatic disease with approved therapies.

             5.2. Cohort 2: HER2 positive (IHC 2+ with FISH confirmation and IHC 3+) gastric
             cancer: patients should have progressed after at least 1 previous HER2 directed
             regimens in metastatic disease with approved therapies.

             5.3. Cohort 3: HER2 low expressing (IHC 1+ and IHC 2+ without FISH confirmation)
             breast cancer: patients should have no available therapy likely to convey clinical
             benefit.

             5.4. Cohort 4: all cancers other than breast cancer with low HER2 expression (IHC 1+
             and IHC 2+ without FISH confirmation) and HER2 positive (IHC 2+ with FISH confirmation
             and Immunohistochemistry (IHC) 3+) cancers other than breast and gastric cancer:
             patients should have no available therapy likely to convey clinical benefit.

          6. Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL.

          7. Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine
             aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN),
             with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and
             patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).

          8. Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease
             Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD)
             formulas. Note that 24 hour urine collection is not required but is allowed.

          9. ECOG Performance Status ≤ 1.

         10. Women of childbearing potential and men must agree to use an approved method of birth
             control (e.g., hormonal, barrier) while receiving study drug, and for at least 7
             months after the last dose of study drug. Women are excluded from birth control if
             they had had tubal ligation or a hysterectomy.

         11. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute
             toxicities from previous therapy, excluding alopecia and vitiligo.

        Exclusion Criteria:

        Phase I:

          1. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure
             (New York Heart Association) III or IV, unstable angina pectoris even if medically
             controlled, history of myocardial infarction during the last 6 months, serious
             arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal
             supraventricular tachycardia).

          2. History of Grade ≥ 3 hypersensitivity reaction to trastuzumab.

          3. History of any toxicity to trastuzumab that resulted in trastuzumab being permanently
             discontinued.

          4. Symptomatic brain metastases or any radiation or surgery for brain metastases within 3
             months of first infusion of study drug.

          5. Require supplemental oxygen for daily activities.

          6. Documented Grade ≥ 2 peripheral neuropathy.

          7. Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy
             treatment within 4 weeks of first infusion of study drug.

          8. Any experimental therapy within 4 weeks of first infusion of study drug.

          9. Any major surgical procedure within 4 weeks of first infusion of study drug.

         10. Diagnosed active liver disease, including viral or other hepatitis, current or history
             of alcoholism, or cirrhosis. Patients who have positive hepatitis B virus test results
             due to having been previously vaccinated against hepatitis B, as evidenced by negative
             hepatitis B surface antigen (HBsAg), negative anti hepatitis B core protein, and
             positive antibody to the HBsAg (anti-HBs) are not excluded.

         11. Have known prior positive test results for human immunodeficiency virus.

         12. Uncontrolled hypertension or diabetes.

         13. Pregnancy or lactation.

         14. Resting corrected QT interval (QTc) > 470 ms at baseline.

         15. Left ventricular ejection fraction (LVEF) < 45% determined by echocardiogram (ECHO) or
             multigated acquisition (MUGA) scan.

         16. Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent.

        Phase II:

          1. Any patient who was treated in the Phase I part of this study.

          2. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure
             (New York Heart Association) III or IV, unstable angina pectoris even if medically
             controlled, history of myocardial infarction during the last 6 months, serious
             arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal
             supraventricular tachycardia).

          3. History of Grade ≥ 3 hypersensitivity reaction to trastuzumab.

          4. History of any toxicity to trastuzumab that resulted in trastuzumab being permanently
             discontinued.

          5. Symptomatic brain metastases or any radiation or surgery for brain metastases within 3
             months of first infusion of study drug.

          6. Require supplemental oxygen for daily activities.

          7. Documented Grade ≥ 2 peripheral neuropathy.

          8. Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy
             treatment within 4 weeks of first infusion of study drug.

          9. Any experimental therapy within 4 weeks of first infusion of study drug.

         10. Any major surgical procedure within 4 weeks of first infusion of study drug.

         11. Diagnosed active liver disease, including viral or other hepatitis, current or history
             of alcoholism, or cirrhosis. Patients who have positive hepatitis B virus test results
             due to having been previously vaccinated against hepatitis B, as evidenced by negative
             hepatitis B surface antigen (HBsAg), negative anti hepatitis B core protein, and
             positive antibody to the HBsAg (anti-HBs) are not excluded.

         12. Have known prior positive test results for human immunodeficiency virus.

         13. Uncontrolled hypertension or diabetes.

         14. Pregnancy or lactation.

         15. Resting QTc > 470 ms at baseline.

         16. LVEF < 45% determined by ECHO or MUGA scan.

         17. Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum Tolerated Dose
Time Frame:Minimum of 21 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Number of patients with dose limiting toxicities

Secondary Outcome Measures

Measure:Phase I: Number of patients with Dose Limiting Toxicities
Time Frame:Minimum of 21 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:
Measure:Phase I: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.
Time Frame:Every 3 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:
Measure:Phase I: Number of participants who developed measurable anti-drug antibodies
Time Frame:Minimum of 21 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:
Measure:Phase II: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.
Time Frame:Minimum of 21 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:
Measure:Phase II: Duration of response (DOR) in patients who responded as determined by RECIST
Time Frame:Minimum of 21 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:
Measure:Phase II: Number of participants who developed measurable anti-drug antibodies
Time Frame:Minimum of 21 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:
Measure:Phase II: Progression Free Survival (PFS)
Time Frame:2 years from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Kaplan Meier Curve for survival without progression in patients who responded to treatment
Measure:Phase II: Overall Survival (OS)
Time Frame:From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Kaplan Meier Curve for survival in all enrolled patients
Measure:Phase I and II: Phase I and II Maximum observed serum or plasma concentration (Cmax).
Time Frame:84 Days from date of first dose
Safety Issue:
Description:
Measure:Phase I and II: Clearance (CL).
Time Frame:84 Days from date of first dose
Safety Issue:
Description:
Measure:Phase I and II: Area under the serum or plasma concentration time curve from 0 to infinity (AUC[0-∞]).
Time Frame:84 Days from date of first dose
Safety Issue:
Description:
Measure:Phase I and II: Terminal phase elimination half life (t½).
Time Frame:84 Days from date of first dose
Safety Issue:
Description:
Measure:Phase I and II: Volume of distribution at terminal phase (Vz).
Time Frame:84 Days from date of first dose
Safety Issue:
Description:
Measure:Phase I and II: Volume of distribution at steady state (Vss).
Time Frame:84 Days from date of first dose
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Klus Pharma Inc.

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