Safety and Tolerability of DS-7423 in Subjects With Advanced Solid Malignant Tumors

• Register: ClinicalTrials.gov
• Last refreshed on: 29 April 2013
• Main ID: NCT01364844
• Date of registration: 31/05/2011
• Primary sponsor: Daiichi Sankyo Inc.
• Public title: Safety and Tolerability of DS-7423 in Subjects With Advanced Solid Malignant Tumors
• Scientific title: A Phase 1, Open-Label, Multiple-Escalating-Dose Study of DS-7423, an Orally Administered Dual PI3K/mTOR Inhibitor, in Subjects With Advanced Solid Tumors
• Date of first enrolment: July 2011
• Target sample size: 66
• Recruitment status: Recruiting
• URL: http://clinicaltrials.gov/show/NCT01364844
• Study type: Interventional
• Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Countries of recruitment

United States

Contacts

• Name: Clinical Trial Information Service for Daiichi Sankyo, Inc.

Key inclusion & exclusion criteria

Inclusion Criteria:

- A pathologically documented advanced solid malignant tumor refractory to standard
treatment or for which no standard treatment is available

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Have adequate bone marrow function, defined as:

Platelet count >= 100 X 10^9/L Hemoglobin (Hb) level >= 9.0 g/dL ANC >= 1.5 X 10^9/L -
Have adequate renal function, defined as: Creatinine clearance >= 60 mL/min, as calculated
using the modified Cockroft Gault equation, ([{140 - age in yrs} x {actual weight in kg}]
divided by [{72 x serum creatinine in mg/dL} multiply by 0.85 if female]), or creatinine
=< 1.5 X ULN

- Have adequate hepatic function, defined as: AST/ALT levels =< 3 X ULN (if liver
metastases are present, =< 5 X ULN) Bilirubin =< 1.5 X ULN

- Have adequate blood clotting function, defined as: Prothrombin time and activated
partial thromboplastin time =< 1.5 X ULN

- Subjects should be able to provide written informed consent, comply with protocol
visits and procedures, be able to take oral medication, and not have any active
infection or chronic comorbidity that would interfere with therapy

- Subjects (male and female) of childbearing potential must agree to use double-barrier
contraceptive measures or avoid intercourse during the study and for 90 days after
the last dose of study drug

- Subjects must be fully informed about their illness and the investigational nature of
the study protocol (including foreseeable risks and possible side effects) and must
sign and date an Institutional Review Board (IRB) approved informed consent form
(ICF) (including Health Insurance Portability and Accountability Act (HIPAA)
authorization, if applicable) before performance of any study-specific procedures or
tests

- Subjects must be willing to provide available preexisting diagnostic or resected
tumor samples, such as formalin-fixed paraffin-embedded sections. Providing fresh
tumor biopsy is optional for subjects in dose escalation cohorts. Pre- and
posttreatment biopsies are optional for all the subjects in Dose Escalation cohorts
but required for those in Dose Expansion cohorts

Additional Inclusion Criteria for Part 2 (Dose Expansion)

- A pathologically documented advanced colorectal or endometrial cancer, with
measurable disease based on RECIST criteria, Version 1.1, that is refractory to
standard treatment

- Agree to undergo pre- and posttreatment tumor biopsies

Exclusion Criteria:

- History of second malignancy and primary central nervous system malignancies, except
adequately treated nonmelanoma skin cancer, curatively treated in situ disease, or
other solid tumors curatively treated, with no evidence of disease for >= 3 years

- Gastrointestinal diseases that could affect the absorption of DS-7423

- Subjects with a fasting glucose > 126 mg/dL (> 7 mmol/L)

- History of diabetes mellitus (Type I or II) or hemoglobin A1c (HbA1c) > 7.0%

- Tested positive for hepatitis B or C serological markers (HBsAg or antiHCV)

- Recipient of live vaccine within 1 month of or during study drug treatment

- Concomitant use of chronic systemic corticosteroids

- Subjects requiring daily supplemental oxygen

- Recipient of a stem cell or bone marrow transplant

- Has a concomitant medical condition that would increase the risk of toxicity, in the
opinion of the investigator or sponsor

- Clinically active brain metastases, defined as untreated and symptomatic, or
requiring therapy with steroids or anticonvulsants to control associated symptoms.
Subjects with treated brain metastases that are no longer symptomatic and who require
no treatment with steroids may be included in the study if they have recovered from
the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed
between the end of whole brain radiotherapy and study enrollment (2 weeks for
stereotactic radiotherapy)

- Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than alopecia) not yet resolved to NCI CTCAE, Version 4.0, grade =< 1 or
baseline. Subjects with chronic grade 2 toxicities may be eligible per the
discretion of the investigator or sponsor (eg, grade 2 chemotherapy-induced
neuropathy)

- Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy,
or hormonal therapy within 3 weeks before study drug treatment; or treatment with
nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment
with small-molecule targeted agents within 2 weeks, or 5 half-lives before study drug
treatment, whichever is longer. Previous and concurrent use of hormone replacement
therapy, the use of gonadotropin-releasing hormone modulators for prostate cancer,
and the use of somatostatin analogs for neuroendocrine tumors are permitted if such
therapy has not been changed within 60 days before study drug treatment

- Therapeutic radiation therapy or major surgery within 4 weeks before study drug
treatment or palliative radiation therapy within 2 weeks before study drug treatment

- Participation in a clinical study within 3 weeks (2 weeks or 5 half-lives, whichever
is longer, for small-molecule targeted agents) before study drug treatment, or
current participation in other investigational procedures

- Concomitant treatment with strong inducers or strong inhibitors of cytochrome P450
(CYP) 3A4/5, and CYP2C8

- Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where
the mean QTcF interval is > 450 millisecond (ms) for males and > 470 ms for females
based on triplicate ECG

- Pregnant or breastfeeding

- Substance abuse or medical, psychological, or social conditions that may, in the
opinion of the investigator, interfere with the subject's participation in the
clinical study or evaluation of the clinical study results

- Prior NCI CTCAE, Version 4.0, grade 3/4 toxicity from a dual phosphatidylinositol 3
kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor (including, but not
limited to, BEZ-235, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384),
requiring dose reduction and/or study discontinuation

Additional Exclusion Criteria for Part 2 (Dose Expansion)

- Prior treatment with a dual PI3K/ mTOR inhibitor (including, but not limited to,
BEZ-235, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384)



Age minimum: 18 Years
Age maximum: N/A
Gender: Both

Health Condition(s) or Problem(s) studied

Colorectal Cancer

Endometrial Cancer

Solid Tumor

Intervention(s)

Drug: DS-7423

Primary Outcome(s)

Adverse Events [Time Frame: 30 days after last dose]

Secondary Outcome(s)

Effects of DS-7423 on glucose metabolism [Time Frame: Cycle 1 Days 1, 2, and 15; and end-of-study]

Part 2 - Objective response rate in subjects with advanced colorectal and endometrial cancer [Time Frame: Baseline and every 2 cycles of treatment for the first 8 cycles and then every 3 cycles thereafter until study drug discontinuation]

Part 2 - Pharmacodynamic effects of DS-7423 in tumors [Time Frame: Baseline and Cycle 1 Day 15]

Pharmacodynamic effects of DS-7423 in surrogate tissues [Time Frame: Cycle 1 Days 1, 2, and 15]

Pharmacodynamic effects of DS-7423 in tumors [Time Frame: Baseline and Cycle 1 Day 4]

Plasma pharmacokinetics of DS-7423 [Time Frame: Cycle 1 - days 1, 2, 8, and 15; Cycle 2 - day 1; end of study]

Secondary ID(s)

DS7423-A-U101

Source(s) of Monetary Support

Please refer to primary and secondary sponsors