Phase 1 Study of PTX-100 in Patients With Advanced Malignancies With PTCL Expansion Cohort

Study Overview
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Brief Summary
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This is an open-label, non-randomized study to evaluate the PD, PK, and safety of 500 to 2000 mg/m2 PTX-100 in patients with advanced malignancies. PTX-100 will be administered by IV infusion over 60 minutes on days 1 to 5 of a 14-day cycle for 4 cycles unless toxicity is observed. Dose escalation is complete and the expansion is open and actively recruiting PTCL patients.

Official Title
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Phase 1 Pharmacodynamic and Pharmacokinetic Study of the Geranylgeranyltransferase I Inhibitor PTX-100 (GGTI-2418) in Patients With Advanced Malignancies

Conditions
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Advanced Cancer, PTCL

Intervention / Treatment
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* Drug: PTX-100


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven multiple myeloma (MM), peripheral T-cell lymphoma (CTCL, AITL or PTCL-NOS), colo-rectal cancer (CRC), pancreas cancer (PANC), or diffuse gastric cancer (DGC) Must have a relapsed or refractory advanced malignancy for which no standard therapy exists. Must have at least 6 unstained slides of archived formalin-fixed, paraffin-embedded tumor tissue available for genotyping studies; if insufficient or no archived tissue is available, a fresh tumor biopsy within 30 days prior to Cycle 1/Day 1 is mandatory. Age ≥ 18 years ECOG performance status ≤ 2 Adequate hematological function: absolute neutrophil count (ANC) ≥ 1000/mm3, platelet count ≥ 50,000 mm3 Adequate hepatic function: total bilirubin ≤ 1.5 times the upper limit of normal (ULN), and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN (patients with liver metastases may be enrolled with elevated hepatic function based on Medical Monitor and Investigator review and agreement) Adequate renal function: measured, calculated or estimated creatinine clearance of ≥ 50 mL/min Female patients of childbearing potential must have a negative serum pregnancy test at screening and agree to use dual methods of contraception. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or postmenopausal. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose. Informed consent (current IRB approved version) must be obtained from the patient or legally authorized representative prior to any study-related procedures. Exclusion Criteria: Radiation, chemotherapy, immunotherapy, or any other approved anticancer therapy ≤ 2 weeks prior to study treatment Participation in another interventional investigational drug study within 4 weeks prior to enrollment Concurrent radiation, chemotherapy, immunotherapy, or any other approved or investigational anticancer therapeutic (Patients are allowed to receive ≤ 10 mg/day corticosteroids for the treatment of non malignant disorders.) Myocardial infarction within 6 months before screening, New York Heart Association Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to first dose (Patients with controlled infection or on prophylactic antibiotics are permitted in the study.) Known to be HIV seropositive Known active hepatitis A, B, or C infection or known to be positive for HCV RNA or HBsAg (HBV surface antigen) Grade > 2 peripheral neuropathy at screening Previous allogeneic transplant within the past 6 months or evidence of clinically significant graft-versus-host disease (if prior bone marrow transplant) Any history of malignancy, other than that treated in this study, unless the patient has remained free of the disease for over 3 years (except for properly treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) Any active medical or psychiatric illness that, in the judgement of the investigator, may interfere with adherence to the protocol Any malignancy with CNS involvement History of allergic reactions attributed to compounds of similar chemical or biologic composition to PTX-100 Female patients who are pregnant or lactating

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTX-100<br>IV infusion over 60 minutes on days 1 to 5 of a 14-day cycle for 4 cycles | Drug: PTX-100<br>* Doses of 500 to 2000 mg/m2 will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigate the time- and dose-dependent PD of multiple doses of PTX-100 in patients with advanced malignancies (RAP-1) | PD endpoints will be based on analysis of level of RAP-1 geranylgeranylation proteins in PBMNCs and tumor biopsies: | One Cycle (cycle = 14 days) | 
| Investigate the time- and dose-dependent PD of multiple doses of PTX-100 in patients with advanced malignancies (PD endpoints) | PD endpoints will be based on analysis of the level of DJ2 farnesylation proteins in PBMNCs and tumor biopsies: | One Cycle (cycle = 14 days) | 
| Investigate the time- and dose-dependent PK of multiple doses of PTX-100 in patients with advanced malignancies (cmax) | Pharmacokinetics will be evaluated by PK parameters calculated from plasma concentrations of PTX 100. Individual and mean plasma concentrations of PTX-100 versus time as well as individual and mean PK parameters will be determined, for the following: • Maximum observed plasma concentration (Cmax) | One Cycle (cycle = 14 days) | 
| Investigate the time- and dose-dependent PK of multiple doses of PTX-100 in patients with advanced malignancies (Tmax) | Pharmacokinetics will be evaluated by PK parameters calculated from plasma concentrations of PTX 100. Individual and mean plasma concentrations of PTX-100 versus time as well as individual and mean PK parameters will be determined, for the following: • Time to maximum observed plasma concentration (Tmax) | One Cycle (cycle = 14 days) | 
| Investigate the time- and dose-dependent PK of multiple doses of PTX-100 in patients with advanced malignancies (half life) | Pharmacokinetics will be evaluated by PK parameters calculated from plasma concentrations of PTX 100. Individual and mean plasma concentrations of PTX-100 versus time as well as individual and mean PK parameters will be determined, for the following: • Apparent elimination half-life (t1/2) | One Cycle (cycle = 14 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PTCL