Phase 1b Study of Indibulin in Combination With Capecitabine in Advanced Solid Tumors

This is a phase 1b study of Indibulin in combination with Capecitabine in advanced solid tumors.

Study Overview

• Status: Unknown
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: indibulin; Drug: capecitabine

Detailed Description

The primary objective of the trial is to determine the maximum tolerated dose (MTD) and optimal dosing schedule of indibulin in combination with capecitabine in subjects diagnosed as having advanced solid tumors.

Secondary objectives include the determination of dose-limiting toxicity (DLT), safety and tolerability, and preliminary activity of this combination. In addition, biological activity of indibulin in combination with capecitabine will be evaluated.

Single arm, open label, Phase Ib, dose-escalation study of indibulin in combination with capecitabine in subjects with advanced histologically confirmed, solid tumors for which no standard therapy exists and for whom treatment with capecitabine is considered medically acceptable.

3 subjects will be treated at each dose level. When DLT occurs in 2 or more of 6 or fewer subjects, MAD has been reached and the dose will be reduced to the previous dosing level, which will be considered the MTD.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Nevada
    • Las Vegas, Nevada, United States
  • Washington
    • Vancouver, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Subjects with advanced, histologically confirmed solid tumors for whom treatment with capecitabine is considered medically acceptable
2. ≥18 years of age
3. ECOG performance score ≤2 (see Appendix 2)
4. Eligible subjects MUST have at least one measurable lesion as defined by RECIST guidelines (see Appendix 3). Measurable lesions MUST NOT have been in a previously irradiated field or injected with biological agents.
5. Life-expectancy ≥12 weeks
6. No more than 2 prior chemotherapy regimens for metastatic disease
7. Subjects on prophylactic anticoagulation (i.e., low-dose warfarin) are eligible provided the coagulation parameter levels are as follows: prothrombin time (INR of prothrombin time) <1.1× institutional ULN

8. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted <2 weeks prior to Study Day 1:

   • Creatinine ≤1.5 × upper limit of normal (ULN) OR a calculated creatinine clearance ≥1.50 cc/min (See Appendix 6 for calculation method)
   • Total bilirubin ≤1.5×ULN
   • Alanine transaminase (ALT) and aspartate transaminase (AST) ≤2.5×ULN (<5×ULN for patients presenting with liver involvement)
   • White blood cell count ≥3.0×109/L
   • Absolute neutrophil count (ANC) ≥1.5×109/L
   • Platelets ≥100×109/L
   • Hemoglobin ≥10 g/dL
9. Written informed consent in compliance with ZIOPHARM policies and the Institutional Review Board (IRB) having jurisdiction over the site
10. Ability and willingness to undergo multiple venous punctures for serum PK sampling
11. For the second phase of the trial (expanded cohort of 10), only capecitabine-naïve subjects will be included; prior therapy with 5-FU will be allowed
12. Each man and woman of childbearing potential must agree to use a reliable method of contraception during the study and for 3 months following his or her last dose of study drug

Exclusion Criteria

1. New York Heart Association (NYHA) functional class ≥3 or myocardial infarction within 6 months (see Appendix 4)
2. Severe renal impairment (creatinine clearance below 30 mL/min)
3. Known dihydropyrimidine dehydrogenase deficiency (DPD)
4. Any evidence of bleeding diathesis or coagulopathy
5. International normalized ration (INR) >1.5, unless the subject is on full-dose warfarin

6. Subjects on full-dose anticoagulants (e.g., warfarin) are eligible provided that both of the following criteria are met:

   • The subject must have an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular-weight heparin
   • The subject must not have any active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
7. Pregnancy and/or lactation. To be enrolled, each woman of childbearing potential must have a negative pregnancy test, which will be repeated at the end of the study.
8. Uncontrolled systemic infection (documented with microbiological studies)
9. Anticancer chemotherapy or immunotherapy within 4 weeks of study entry or at any time during the study or investigational drug therapy outside of this trial during or within 4 weeks of study entry
10. Mitomycin C or nitrosureas should not be given within 6 weeks of study entry.
11. Radiotherapy within 3 weeks of study entry or at any time during the study. For target lesions that have been radiated within 3 months of study entry, only those lesions with documented progression post radiation will be allowed.
12. Surgery within 4 weeks of start of study drug dosing, excluding tumor biopsy for pharmacodynamic parameters
13. History of an invasive second primary malignancy diagnosed within the previous 3 years except for Stage I endometrial/cervical carcinoma or prostate carcinoma treated surgically, and non-melanoma skin cancer
14. Substance abuse or medical, psychological or social conditions that may interfere with the subject's participation in the study or the evaluation of study results
15. Any condition that is unstable or could jeopardize the safety of the subject and his/her compliance with study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: single; Single arm designed to elicit Maximum Tolerated Dose	Drug: indibulin; indibulin, dose escalation, 400-600 mg taken twice every day; Drug: capecitabine; capecitabine, dose escalation, 875 mg/m2- 1250 mg/m2, taken twice daily for 14 days per 21 day cycle; Other Names: Xeloda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
toxicities	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
pharmacokinetics	6 months

Collaborators and Investigators

• Sponsor: Alaunos Therapeutics
• Investigators: Study Chair: Jonathan Lewis, MD, Alaunos Therapeutics

Publications and helpful links

General Publications

• Kapoor S, Srivastava S, Panda D. Indibulin dampens microtubule dynamics and produces synergistic antiproliferative effect with vinblastine in MCF-7 cells: Implications in cancer chemotherapy. Sci Rep. 2018 Aug 17;8(1):12363. doi: 10.1038/s41598-018-30376-y.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Anticipated): June 1, 2013
• Study Completion (Anticipated): June 1, 2013

Study Registration Dates

• First Submitted: July 29, 2008
• First Submitted That Met QC Criteria: July 29, 2008
• First Posted (Estimate): August 1, 2008

Study Record Updates

• Last Update Posted (Estimate): July 19, 2012
• Last Update Submitted That Met QC Criteria: July 18, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Cancer; Capecitabine; Xeloda; Indibulin
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine
• Other Study ID Numbers: IBL1005