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Phase 1/2 Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523, an ERK 1/2 Inhibitor, in Patients With Advanced Malignancies


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Advanced Solid Tumors

Thank you

Trial Information

Phase 1/2 Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523, an ERK 1/2 Inhibitor, in Patients With Advanced Malignancies


The study is being performed to assess the safety and tolerability of BVD-523 given orally,
twice daily for 21-day cycles.

In Part 1 of the study, an accelerated dose escalation plan will be used to establish dose
limiting toxicities (DLT), maximum tolerated dose (MTD), and the recommended Phase 2 dose
(RP2D).

In Part 2 of the study, additional patients with particular tumor types and/or cancers
harboring specific genetic mutations will be recruited for treatment at the Recommended
Phase 2 Dose (RP2D). Patients may also be assessed pharmacodynamic measures in healthy or
malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic
measures.


Inclusion Criteria:



- Patients with metastatic or advanced-stage malignant tumor, confirmed histologically,
for whom no therapy exists that would be curative. Patients may have received up to 2
prior lines of chemotherapy for their metastatic disease.

- ECOG performance status of 0 or 1

- Predicted life expectancy of ≥ 3 months

- Adequate bone marrow, liver and renal function renal function as assessed by the
following laboratory requirements:

1. creatinine ≤ 1.5 times ULN (upper limit of normal)] and/or GFR of ≥ 50mL/min

2. total bilirubin ≤ 1.5 x UNL; AST (aspartate transaminase) and/or ALT (alanine
transaminase) ≤ 3x UNL or ≤ 5 x UNL if due to liver involvement by tumor

3. hemoglobin ≥ 9.0 g/dL; platelets ≥ 100 x 10 cells/L; absolute neutrophil count ≥
1.5 x 109 cells/L

- Adequate cardiac function, e.g. [left ventricular ejection fraction (LVEF) of > 50%;
corrected QT interval (QTc) < 470 ms]

- For women: Negative pregnancy test for females of child-bearing potential; must be
surgically sterile, postmenopausal, or compliant with a contraceptive regimen during
and for 3 months after the treatment period.

- For men: Must be surgically sterile, or compliant with a contraceptive regimen during
and for 3 months after the treatment period.

- For Part 2 of the Study ONLY patients must have measurable disease by RECIST 1.1 and
be in one of the following 4 groups:

1. Patients with BRAF mutated melanoma; not previously treated with inhibitors of
BRAF, MEK, or ERK

2. Patients with BRAF mutated melanoma who have progressed while being treated with
BRAF inhibitors.

3. Patients with BRAF mutated non-melanoma; not previously treated with inhibitors
of BRAF, MEK, or ERK

4. Patients with RAS mutated advanced malignancy; not previously treated with
inhibitors of BRAF, MEK, or ERK

Exclusion Criteria:

- Gastrointestinal (GI) condition which could impair absorption of study medication

- Uncontrolled or severe intercurrent medical condition

- Known uncontrolled brain metastases. Stable brain metastases either treated or being
treated with a stable dose of steroids/anticonvulsants, with no dose change in the
previous 4 weeks, can be allowed

- Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic
or immunotherapy, etc.) within 28 days or 5 half-lives, whichever is shorter

- Major surgery within 4 weeks prior to first dose

- Any use of an investigational drug within 28 days or 5 half-lives (whichever is
shorter) prior to the first dose of BVD-523. A minimum of 10 days between termination
of the investigational drug and administration of BVD-523 is required. In addition,
any drug- related toxicity except alopecia should have recovered to Grade 1 or less

- Pregnant or breast-feeding women

- Any evidence of serious active infections

- Any important medical illness or abnormal laboratory finding that would increase the
risk of participating in this study

- A history or current evidence/risk of retinal vein occlusion (RVO) or central serous
retinopathy (CSR)

- Concurrent therapy with any other investigational agent

- Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, or
CYP3A4, or strong inducers of CYP3A4.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Determination of recommended phase 2 dose (RP2D) of BVD-523 determined by dose-limiting toxicities.

Outcome Time Frame:

Until safety and tolerability limit further dose escalation; up to ~18 months

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

BVD-523-01

NCT ID:

NCT01781429

Start Date:

March 2013

Completion Date:

March 2015

Related Keywords:

  • Advanced Solid Tumors

Name

Location

Massachusetts General Hospital (MGH)Boston, Massachusetts  02114
UCLA Med-Hematology & OncologyLos Angeles, California  90095
Sarah Cannon Research Institute/Yale Cancer CenterNew Haven, Connecticut  06520
Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)Sarasota, Florida  34232
Sarah Cannon Research Institute Hospital at VanderbiltNashville, Tennessee  37203