Clinical trial NCT03602079: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
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
Lead sponsor: Klus Pharma Inc.
Sponsor class: INDUSTRY
First posted: 2018-07-26
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).

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.

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.

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose
timeFrame: 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
Secondary outcomes:
measure: Phase I: Number of patients with Dose Limiting Toxicities
timeFrame: 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
measure: Phase I: Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.
timeFrame: 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
measure: Phase I: Number of participants who developed measurable anti-drug antibodies
timeFrame: 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
measure: Phase I Maximum observed serum or plasma concentration (Cmax).
timeFrame: 84 Days from date of first dose
measure: Phase I Clearance (CL).
timeFrame: 84 Days from date of first dose
measure: Phase I Area under the serum or plasma concentration time curve from 0 to infinity (AUC[0-∞]).
timeFrame: 84 Days from date of first dose
measure: Phase I Terminal phase elimination half life (t½).
timeFrame: 84 Days from date of first dose
measure: Phase I Volume of distribution at terminal phase (Vz).
timeFrame: 84 Days from date of first dose
measure: Phase I Volume of distribution at steady state (Vss).
timeFrame: 84 Days from date of first dose
Other outcomes:
Locations:
city: Sarasota
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center Cancer Center
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Lake Success
country: United States
facility: Clinical Research Alliance, Inc.
state: New York
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Cancer Institute
state: Oregon
city: Dallas
country: United States
facility: Mary Crowley Cancer Research Centers - Medical City
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics, LLC (START)
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialist
state: Virginia
Study officials:
affiliation: MD Anderson
name: Jordi Rodon Ahnert, MD, PhD
role: STUDY_CHAIR
References: