Study Evaluating GZ17-6.02 in Patients With Advanced Solid Tumors or in Combination With Capecitabine in Metastatic Hormone Receptor Positive Breast Cancer

A Phase I/Ib, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of GZ17-6.02 Monotherapy and in Combination With Capecitabine, Given Orally on a Daily Schedule in Patients With Advanced Solid Tumors or Lymphoma

This Phase I/Ib study is a Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic and Pharmacokinetic Study of GZ17-6.02 Monotherapy and in Combination with Capecitabine, Given Orally on a Daily Schedule in Patients with Advanced Solid Tumors or Lymphoma

This study will evaluate the safety, pharmacokinetics, and pharmacodynamic effects of a novel anti-cancer drug, GZ17-6.02 administered to patients with advanced solid tumors or lymphoma, which have progressed after receiving standard/approved therapy or where there is no approved therapy.

This study will determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of GZ17-6.02 monotherapy and in combination with standard-of-care oncology treatments and to establish the dose of GZ17-6.02 recommended for future monotherapy and combination therapies phase II oncology clinical studies.

General Inclusion Criteria:

• Patients with a pathologically confirmed diagnosis of advanced solid tumors or lymphoma.

• Tumor progression after receiving standard/approved therapies which may include chemotherapy, targeted agents, radio-immuno conjugates, check point inhibitors, where there is no approved therapy; or the patient is intolerant of standard of care or the patient declines standard of care treatment

• One or more metastatic tumors measurable, or evaluable, per RECIST v1.1 Criteria for solid tumors and Lugano Criteria for lymphoma

• Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1

• Life expectancy of at least 3 months

• Age 18 years

• Signed, written IRB-approved informed consent

• A negative pregnancy test (if female)

• Acceptable liver function:

  • Bilirubin ≤ 1.5 times upper limit of normal
  • AST (SGOT), ALT (SGPT) and Alkaline phosphatase ≤ 2.5 times upper limit of normal (if liver metastases are present, then ≤ 5 x ULN is allowed)

• Acceptable renal function:

  o Serum creatinine ≤ 1.5 times institutional ULN, OR calculated creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.

• Acceptable hematologic status:

  • Granulocyte ≥ 1500 cells/mm3
  • Platelet count ≥ 100,000 (plt/mm3)
  • Hemoglobin ≥ 9 g/dL

• Urinalysis:

  o No clinically significant abnormalities

• Acceptable coagulation status (for patients on warfarin or other anti-coagulants, a PT/PTT considered by the PI as therapeutically appropriate will be allowed):

  • PT within ≤ 1.5 times normal limits
  • PTT within ≤ 1.5 times normal limits

• For men and women of child-producing potential, the use of effective contraceptive methods during the study

• Fasting glucose ≤ 180 mg/dL

• Albumin ≥ 3.0 g/dL within seven days of initiating protocol treatment

For patients in the GZ17-6.02 plus capecitabine Phase 1b Expansion Cohort 2 (metastatic breast cancer):

• Pathologically confirmed diagnosis of HER2-negative and Hormone Receptor (HR) (estrogen receptor [ER] and/or progesterone receptor)-positive metastatic breast cancer;
• Had ≤ 1 prior treatment (not including neoadjuvant or adjuvant treatment);
• Are naïve to capecitabine but not necessarily to fluorouracil (5 FU);
• Eligible for standard-of-care treatment with capecitabine monotherapy.
• Patients in Expansion Cohort 2 with bone-only metastatic disease must have one or more lytic or a mixed lytic-blastic lesions that can be assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI).

For patients in GZ17-6.02 plus capecitabine Phase 1b Expansion Cohort 3 (metastatic colorectal cancer):

• Pathologically confirmed diagnosis of metastatic colorectal cancer;
• Had ≤ 2 prior treatments (not including neoadjuvant or adjuvant treatment);
• Are naïve to capecitabine but not necessarily to 5 FU;
• Eligible for standard-of-care treatment with capecitabine monotherapy.

General Exclusion Criteria: (All patients, unless otherwise specified):

• New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.
• Currently taking MAOIs
• Baseline QTc exceeding 450 msec in males, 470 msec in females (using the Fridericia's formula) and/or patients receiving class 1A or class III antiarrhythmic agents;
• Known active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy;
• Pregnant or nursing women.
• NOTE: Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; or abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Treatment with radiation therapy or surgery within 1 month prior to study entry.
• Treatment with chemotherapy, targeted therapeutics (e.g. tyrosine kinase inhibitors, therapeutic antibodies, etc), or investigational therapies within 1 month, or 5 half-lives (whichever is shorter), prior to study entry (6 weeks for nitrosoureas or mitomycin C). For radiopharmaceuticals, within 1 month unless hematopoietic recovery has not returned to pretreatment baseline;
• Unwillingness or inability to comply with procedures required in this protocol;
• Known active infection with HIV, HTLV-1, hepatitis B, hepatitis C or other chronic viral infections that could interfere with the interpretation of study data;
• Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor.
• Patients who are currently receiving any other investigational agent;
• Primary Central Nervous System (CNS) malignancies;
• Active CNS metastases requiring treatment or radiotherapy, or which have not been confirmed stable on radiographic imaging for ≥30 days prior to C1D1;
• Patients requiring steroids for neurological signs and symptom stabilization.
• Patients who are unable to successfully discontinue all prohibited medications listed in Appendix 6;
• Patients must not have received a transfusion (platelets or red blood cells) ≤ 2 weeks prior to initiating protocol therapy.

For patients in the GZ17-6.02 monotherapy Dose Escalation Cohort and patients in Expansion Cohort 1:

• Patients with cow's milk allergy or with galactosemia

Phase 1b Expansion Cohort 2 (metastatic breast cancer) and Expansion Cohort 3 (metastatic colorectal cancer):

• Any history of coronary artery disease is exclusionary; New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on the ECG.

• Any conditions or medications that are contraindicated with capecitabine dosing;

• Dihydropyrimidine dehydrogenase (DPD) deficiency;

• Known sensitivity to capecitabine or any of its components or to 5-FU ;

• Serious nonmalignant disease (e.g., hydronephrosis, liver failure, or other conditions) that could compromise protocol objectives in the opinion of the investigator and/or the sponsor

  o This includes prior gastrointestinal surgery that would interfere with the oral drug absorption.

• Malignancy other than metastatic breast cancer (Expansion Cohort 2) or metastatic colorectal cancer (Expansion Cohort 3) that required therapy within the preceding 5 years, other than adequately treated:

  • non-melanoma skin cancer or in situ cancer;
  • another cancer that has a very low risk of interfering with the safety or efficacy endpoints of the study, must be approved by the Sponsor medical team.