ZW25 in Women With Endometrial Cancers
ZW25 in Women With Endometrial Cancers
This study is being done to test the drug ZW25 and look at whether this drug is effective in
 women with HER2-overexpressed endometrial cancer or carcinosarcoma that has been treated in
 the past.
Inclusion Criteria:

 -  Patients must be enrolled or agree to consent to the companion genomic profiling study
 MSKCC IRB# 12-245 Part A. Results are not required prior to initiating treatment on
 protocol, unless patients do not have other test results by IHC or FISH confirming
 HER2 overexpression.

 -  Patients must have recurrent or persistent HER2 overexpressing endometrial cancer or
 endometrial carcinosarcoma. HER2 overexpression is defined as 3+ by IHC or 2+ with
 gene amplification by FISH (HER2/CEP17 ratio ≥ 2) or HER2 amplified (fold change ≥ 2)
 on MSK IMPACT.

 -  Histologic documentation of diagnosis of endometrial carcinoma or carcinosarcoma is
 required.

 -  Age ≥ 18 years

 -  Patients must have had at least one but no more than two prior chemotherapeutic
 regimens for management of endometrial carcinoma (including neo-adjuvant and/or
 adjuvant chemotherapy). Initial treatment may include chemotherapy, chemotherapy and
 radiation therapy, and/or consolidation/maintenance therapy. Chemotherapy administered
 in conjunction with primary radiation as a radio-sensitizer WILL be counted as a
 systemic chemotherapy regimen. Prior hormonal therapy will not count as a prior
 regimen. Prior treatment with trastuzumab is allowed.

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

 -  LVEF ≥ 50% on baseline screening ECHO.

 -  Resolution of adverse effects of recent surgery, radiotherapy, or chemotherapy to
 Grade ≤ 1 prior to first study treatment (with the exception of alopecia or clinically
 insignificant laboratory values).

 -  Patients must have measurable disease. Measurable disease is defined by RECIST
 (version 1.1). Measurable disease is defined as at least one lesion that can be
 accurately measured in at least one dimension (longest diameter to be recorded). Each
 non-nodal lesion must be 10 mm when measured by CT, MRI or caliper measurement by
 clinical exam; or 20 mm when measured by chest x-ray. Lymph nodes must be ≥ 15 mm in
 short axis when measured by CT or MRI.

 -  No active infection requiring antibiotics (with the exception of uncomplicated urinary
 tract infection).

 -  Patients must be willing to provide an archival tumor block or tissue slides (at least
 10-20 FFPE slides).

 -  All patients must consent to mandatory pre-treatment and post-treatment core needle
 biopsies.

 -  Patients must have adequate hematological, liver, cardiac and kidney function within
 14 days prior to first treatment:

 1. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (> 1500 per mm^3)

 2. Platelet ≥ 100 X 109/L (>100,000 per mm^3)

 3. Hemoglobin ≥ 8.0 g/dL

 4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). (Unless
 Gilbert's Syndrome, for which Bilirubin ≤ 3 x institutional upper limit of normal
 (ULN), without concurrent clinically significant liver disease) AST (SGOT)/ALT
 (SGPT) ≤ 3 x institutional upper limit of normal (ULN) unless liver metastases
 are present, in which case it must be ≤ 5x ULN.

 5. Serum creatinine ≤ 1.5 x institutional upper limit of normal (ULN).

 -  For patients of childbearing potential, agreement to use two effective forms of
 contraception (e.g., surgical sterilization, a reliable barrier method, birth control
 pills, or contraceptive hormone implants) and to continue its use for the duration of
 the study and for 12 weeks after the last ZW25 dose.

 -  Agree to practice total abstinence when this is in line with the preferred and usual
 lifestyle of the subject.

 1. A woman is considered to be of childbearing potential unless 1 of the following
 applies: She is considered to be permanently sterile. Permanent sterilization
 methods include hysterectomy, bilateral salpingectomy, tubal ligation, and
 bilateral oophorectomy.

 2. She is postmenopausal, defined as no menses for 12 months without an alternative
 medical cause. A high follicle-stimulating hormone (FSH) level consistently in
 the postmenopausal range (30 mIU/mL or higher) may be used to confirm a
 postmenopausal state in women not using hormonal contraception or hormonal
 replacement therapy; however, in the absence of 12 months of amenorrhea, a single
 FSH measurement is insufficient to confirm a postmenopausal state.

 3. Female patients of childbearing potential must have a negative serum pregnancy
 test result less than 3 day prior to administration of the first dose of study
 treatment.

 Patients or their legally authorized representative (LAR) must be willing and able to sign
 the informed consent form, and to adhere to the study visit schedule and other protocol
 requirements.

 Exclusion Criteria:

 -  Women who are pregnant or lactating or women of childbearing potential (WCBP) not
 protected by highly-effective contraceptive methods.

 -  > Grade 1 peripheral neuropathy.

 -  History of hemorrhagic or ischemic stroke within the prior six months.

 -  History of NYHA Class II-IV heart failure, no serious arrhythmia.

 -  History of MI or unstable angina within 6 months of study initiation.

 -  Patients with a lifetime cumulative dose of anthracycline >300 mg/m2 or who have
 received anthracycline treatment within 90 days of the expected first dose of ZW25 are
 not eligible for treatment.

 -  Prior hypersensitivity to monoclonal antibodies.

 -  Active hepatitis B or hepatitis C infection. Patients with previously resolved
 hepatitis B infection are eligible. Presence of positive test results for hepatitis B
 infection who have resolved the infection (defined by positive for HB surface antibody
 (anti-HBs) and polymerase chain reaction (PCR) assay is negative for HBV DNA are
 eligible. Patients positive for HCV antibody are eligible only if testing for HCV RNA
 is negative.

 -  Known HIV infection.

 -  Current severe, uncontrolled systemic disease (e.g., clinically significant
 cardiovascular, pulmonary, or metabolic disease).

 -  Major surgical procedure or significant traumatic injury within 28 days prior to Day 1
 or anticipation of the need for major surgery during the course of study treatment.

 -  Known untreated or active central nervous system (CNS) metastases (progressing or
 requiring anticonvulsants or corticosteroids for symptomatic control) leptomeningeal
 carcinomatosis.

 Patients with a history of treated CNS metastases are eligible, provided that they meet all
 of the following criteria:

 1. Presence of measurable disease outside the CNS

 2. No radiographic evidence of worsening upon the completion of CNSdirected therapy and
 no evidence of interim progression between the completion of CNS-directed therapy and
 the screening radiographic study

 3. No history of intracranial hemorrhage or spinal cord hemorrhage

 4. No ongoing requirement for dexamethasone as therapy for CNS disease (anticonvulsants
 at a stable dose are allowed)

 5. Absence of leptomeningeal disease

 -  Inability to comply with study and follow-up procedures.

 -  Known allergy or hypersensitivity to the components of ZW25 formulation.

 -  Any other disease, metabolic dysfunction, physical examination finding, or
 clinical laboratory finding that, in the investigator's opinion, gives reasonable
 suspicion of a disease or condition that contraindicates the use of an
 investigational drug or that may affect the interpretation of the results or
 render the patient at high risk from treatment complications.

 -  Active or history of inflammatory bowel disease (IBD)

 -  Severe infections within 4 weeks prior to initiation of study drug treatment,
 including but not limited to hospitalization for complications of infection,
 bacteremia, or severe pneumonia.

 -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to
 initiation of study treatment. Patients receiving prophylactic antibiotics (e.g.,
 for prevention of urinary tract infection or to prevent chronic obstructive
 pulmonary disease exacerbation) are eligible for the study. Patients receiving
 antibiotic treatment for urinary tract infection are also eligible.

 -  Administration of a live attenuated vaccine within 4 weeks prior to initiation of
 study treatment or anticipated need for such a vaccine during study. Patients
 must agree not to receive live, attenuated influenza vaccine (e.g., Flumist®)
 within 4 weeks prior to treatment.)

 -  Participation in another clinical study with receipt of an investigational
 product during the last 4 weeks.

 -  History of another primary malignancy except for:

 a. Malignancy treated with curative intent and with no known active disease ≥ 2 years
 before the first dose of study drug and of low potential risk for recurrence. b. Adequately
 treated non-melanoma skin cancer or lentigo maligna without evidence of disease. c.
 Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in
 situ). d. Adequately treated stage 1 breast cancer.

 -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted
 therapy, biologic therapy, tumor embolization, monoclonal antibodies) < 21 days prior
 to the first dose of study drug. Receipt of the last dose of hormonal therapy within <
 7 days prior to the first dose of study drug.

 -  Any prior radiation therapy must be discontinued at least four weeks prior to
 registration. QT interval corrected for heart rate (QTc) ≥ 470 ms on screening
 electrocardiograms (ECG).

 -  History of small or large bowel obstruction within 3 months of registration, including
 subjects with palliative gastric drainage catheters. Subjects with palliative
 diverting ileostomy or colostomy are allowed if they have been symptom free for more
 than 3 months.

 -  Subjects with refractory ascites, defined as ascites needing drainage catheter or
 therapeutic paracentesis more often than every 4 weeks.

 -  Ongoing bowel perforation or presence of bowel fistula or abscess within 3 months of
 registration.