Portland, Oregon 97213

  • Rare Disea

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.


Study summary:

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).


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.


Study is Available At:


Original ID:

KlusPharma


NCT ID:

NCT03602079


Secondary ID:


Study Acronym:


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


Overall Status:

Recruiting


Study Phase:

Phase 1/Phase 2


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Klus Pharma Inc.


Oversight Authority:

There was an error processing this request


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

5


Number of Groups:

0


Total Enrollment:

82


Enrollment Type:

Anticipated


Overall Contact Information

Official Name:Jordi Rodon Ahnert, MD, PhD
Study Chair
MD Anderson
Primary Contact:Clinical Trials Info at Kluspharma
609-662-1913
Clinicaltrialinfo@kluspharma.com

Study Dates

Start Date:July 16, 2018
Completion Date:May 2021
Completion Type:Anticipated
Primary Completion Date:October 2020
Primary Completion Type:Anticipated
Verification Date:March 2019
Last Changed Date:March 11, 2019
First Received Date:July 6, 2018

Study Outcomes

Outcome Type:Primary Outcome
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
Safety Issues:False
Description:Number of patients with dose limiting toxicities
Outcome Type:Primary Outcome
Measure:Phase II: Percentage of patients with an Objective Response Rate (ORR) [Complete Response (CR) + Partial Response (PR)]
Time Frame:From date of enrollment until the date of first documented progression or date of death from any cau
Safety Issues:False
Description:Objective Response Rate as determined by RECIST which will be complete response (CR) + partial response (PR)
Outcome Type:Secondary Outcome
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
Safety Issues:False
Outcome Type:Secondary Outcome
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 deat
Safety Issues:False
Outcome Type:Secondary Outcome
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
Safety Issues:False
Outcome Type:Secondary Outcome
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
Safety Issues:False
Outcome Type:Secondary Outcome
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
Safety Issues:False
Outcome Type:Secondary Outcome
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
Safety Issues:False
Outcome Type:Secondary Outcome
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
Safety Issues:False
Description:Kaplan Meier Curve for survival without progression in patients who responded to treatment
Outcome Type:Secondary Outcome
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 cau
Safety Issues:False
Description:Kaplan Meier Curve for survival in all enrolled patients
Outcome Type:Secondary Outcome
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 Issues:False
Outcome Type:Secondary Outcome
Measure:Phase I and II: Clearance (CL).
Time Frame:84 Days from date of first dose
Safety Issues:False
Outcome Type:Secondary Outcome
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 Issues:False
Outcome Type:Secondary Outcome
Measure:Phase I and II: Terminal phase elimination half life (t½).
Time Frame:84 Days from date of first dose
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Phase I and II: Volume of distribution at terminal phase (Vz).
Time Frame:84 Days from date of first dose
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Phase I and II: Volume of distribution at steady state (Vss).
Time Frame:84 Days from date of first dose
Safety Issues:False

Study Interventions

Intervention Type:Drug
Name:A166
Description:A166 is an Antibody Drug Conjugate (ADC) targeting HER2 expressing cancer cells.
Arm Name:Phase I: Dose Escalation

Study Arms

Study Arm Type:Experimental
Arm Name: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
Study Arm Type:Experimental
Arm Name:Phase II: • Cohort 1
Description:HER2 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.
Study Arm Type:Experimental
Arm Name:Phase II: • Cohort 2
Description:HER2 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.
Study Arm Type:Experimental
Arm Name:Phase II: • Cohort 3
Description:HER2 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.
Study Arm Type:Experimental
Arm Name:Phase II: • Cohort 4
Description:All 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.

Study Agencies

Agency Class:Industry
Agency Type:Lead Sponsor
Agency Name:Klus Pharma Inc.

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: April 03, 2020

Modifications to this listing: Only selected fields are shown, please use the link below to view all information about this clinical trial.


If you would like to be contacted by the clinical trial representative please fill out the form below.