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

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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

Brief Summary

      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).
    

Study Phase

Phase 1/Phase 2

Study Type

Interventional


Primary Outcome

Phase I: Maximum Tolerated Dose

Secondary Outcome

 Phase I: Number of patients with Dose Limiting Toxicities

Condition

HER2-positive Breast Cancer

Intervention

A166

Study Arms / Comparison Groups

 Phase I: Dose Escalation
Description:  Six 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

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

82

Start Date

July 16, 2018

Completion Date

December 2022

Primary Completion Date

April 2022

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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Jordi Rodon Ahnert, MD, PhD, 609-662-1913, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03602079

Organization ID

KlusPharma


Responsible Party

Sponsor

Study Sponsor

Klus Pharma Inc.


Study Sponsor

Jordi Rodon Ahnert, MD, PhD, Study Chair, MD Anderson


Verification Date

August 2021