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ZIOPHARM Oncology, Inc.
1 First Avenue
Parris Building, #34
Navy Yard PlazaBoston, MA 02129Main 617-259-1970Fax 617-241-2855 Indibulin, a Novel Tubulin Targeting-Agent, in Combination with Capecitabine,
is Suitable for Mathematically-Optimized Dose-Scheduling
Jonathan J. Lewis1, Matthew D. Galsky2, 6, Luis H. Camacho3, David M. Loesch4, 6, Philip B. Komarnitsky1, Barbara Wallner1, Jan Stevens1, Larry Norton5.
1ZIOPHARM Oncology, New York, NY; 2Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 3Oncology Consultants P.A., Houston, TX; 4Central Indiana Cancer Centers, Indianapolis, IN; 5Harmon Hill, New York, NY; 6US Oncology, Translational Oncology Program, Houston, TX.
Clinical: Key Inclusion Criteria
Preliminary Clinical Activity
Indibulin: Optimization of Dosing Schedules
Background: Indibulin (IDB) is a novel, orally available tubulin-targeting
• Histologically confirmed solid tumors for whom treatment with Median SD 6 Cycles
molecule that perturbs cancer cell migration and mitosis. It is active capecitabine is considered medically acceptable • Breast and colon cancer SD for 9 Cycles Indibulin 22 kg/kg/day
against taxane-resistant cell lines and is synergistic with 5-FU in vitro and • No more than 2 prior chemotherapy regimens for metastatic disease in vivo. Two translational studies have been conducted: a Phase IB study (Actual slope)
(Expected slope)
of IDB in combination with capecitabine (CAP) in patients with advanced • Adequate bone marrow, liver and renal function solid tumors, and mathematical modeling applying Norton-Simon models Daily Oral Therapy
to breast carcinoma MX-1 xenografts to further develop Phase II dose.
Breast and Colon Cancer
IDB is administered continuously starting at 400 mg BID. CAP • ≥18 years of age. ECOG performance score ≤2; life expectancy ≥12 weeks is administered for 2 weeks with 1 week rest, starting at 875 mg/m2 BID.
IDB and CAP are escalated to the highest planned dose level (not MTD): Bladder and Prostate Cancer
IDB 600 mg BID & CAP 1000 mg/m2 BID. Efficacy is evaluated every 9 weeks
using RECIST. In the xenograft model indibulin is administered at dose levels MX-1 Xenograft
from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma.
0 5 10 15 20 25 30 35
Key Exclusion Criteria
Days of growth
Tumor growth is analyzed using a Gompertzian-type growth model to determine via calculus of variations the optimal schedule to maximize the Preliminary Safety
• New York Heart Association (NYHA) functional class ≥3 or myocardial AEs that are related and occurred in 2 or more pts (≥ 29%) Results:
infarction ≤6 months, systemic infection To date, 7 patients have been treated and are evaluable for safety.
Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are Frequency, (%)
• Severe renal impairment (creatinine clearance below 30 mL/min) evaluable for efficacy and all have stable disease (3 for 6+ cycles, 1 for 3 Grade 1/2 AEs that Were Related
cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting, • Known dihydropyrimidine dehydrogenase deficiency (DPD) anorexia, and headache. DLTs have not been observed. In MX-1 xenografts, • Radiotherapy ≤3 weeks. Any other anticancer, investigational drug, or indibulin demonstrates linear dose-efficacy relationship over the range of immunological therapy ≤4 weeks. Surgery ≤4 weeks excluding tumor 12 to 22 mg/kg. At all dose levels the first 5 days of administration are associated with a rapid accumulation of anticancer effect with lesser MX-1 Xenograft
effects over the next 5 days to a peak of efficacy at day 10.
• History of invasive second primary malignancy diagnosed within 3 years 0 5 10 15 20 25 30 35
Days of growth
(except: Stage I endometrial/cervical carcinoma or prostate carcinoma IDB + CAP is well tolerated. There is preliminary evidence Grade 3/4 AEs that Were Related
treated surgically, or non-melanoma skin cancer) of clinical activity even with this sub-optimal, continuous schedule of IDB.
Formal analyses suggest that an intermittent schedule could optimize efficacy, minimize acquired resistance and allow for host recovery from drug- induced toxicity. Pre-clinical evaluation in a breast cancer model supports Conclusions
an intermittent dosing schedule to further increase the activity of IDB. Clinical: Dosing Schedule
Norton-Simon Modeling
• Oral indibulin in combination with capecitabine is very well tolerated with no neurotoxicity. Early activity in breast, colon, bladder, and • Capecitabine (875 mg/m2 BID) given for 2 weeks followed by a 1-week
rest, and indibulin (400 mg BID, starting dose level) given every day • Determine form and parameters of unperturbed growth curve* continuously, until disease progression or unacceptable toxicity occurs • Formal analyses of preclinical data utilizing Norton-Simon Modeling • Assess degree of deviation (as differential equation) after growth reveals that the major effect of therapy occurs in five days of exposure, • To evaluate the combination of oral indibulin and capecitabine in subjects • Three patients in each cohort. If a DLT occurs the cohort is expanded perturbation by various schedules of therapy which is not manifest on gross inspection until one week thereafter.
• Determine points of maximal change in rate of perturbation Hence, an intermittent schedule based on five days of drug administration preserves full activity while minimizing toxicity. This may also minimize • Predict minimal exposure to create maximum effect Dose Level Cohort
875 mg/m2 BID
• To determine the most efficacious dosing strategy for oral indibulin using • A Phase I-II study in breast cancer using this novel scheduling strategy 875 mg/m2 BID



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