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FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer. - Clinical cancer research : an official journal of the American Association for Cancer Research
On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCEÂ®, Pfizer Inc.), an inhibitor of cyclin dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label Phase 1/2 trial (PALOMA-1) in 165 patients randomized to palbociclib (125mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5mg orally daily) or letrozole alone. The Phase 2 portion of the trial was divided into two cohorts: Cohort 1 enrolled 66 biomarker-unselected patients and Cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared to patients receiving letrozole alone [HR 0.488 (95% CI: 0.319, 0.748)]. Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 which may be contingent upon verification and description of clinical benefit in the on-going and fully accrued confirmatory trial, PALOMA-2.Copyright Â© 2015, American Association for Cancer Research.
Pathological complete response in neoadjuvant treatment of breast cancer. - Annals of surgical oncology
There has been recent interest in using pathological complete response (pCR) as a potential surrogate endpoint for long-term outcomes in the neoadjuvant treatment of high-risk, early-stage breast cancer.We review the clinical trials that have contributed to our understanding of the association between pCR and long-term outcomes, describe the various definitions of pCR, describe patient populations in which pCR may predict long-term benefit, and discuss the implications of pCR on drug development and accelerated approval for neoadjuvant treatment of breast cancer.Varying definitions of pCR across clinical trials conducted in heterogeneous patient populations make understanding the association of pCR with long-term outcomes challenging. The US Food and Drug Administration established the Collaborative Trials in Neoadjuvant Breast Cancer group to evaluate the potential use of pCR as a regulatory endpoint. The group demonstrated that pCR defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0) provided a better association with improved outcomes compared to eradication of invasive tumor from the breast alone (ypT0/is).Even though pCR was not validated as a surrogate endpoint for long-term outcomes, the promising data regarding the strong association of pCR with substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer supported the opening of an accelerated approval pathway for patients with high-risk, early-stage breast cancer.
First FDA approval of neoadjuvant therapy for breast cancer: pertuzumab for the treatment of patients with HER2-positive breast cancer. - Clinical cancer research : an official journal of the American Association for Cancer Research
On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab-docetaxel (TD), pertuzumab-trastuzumab-docetaxel (PTD), pertuzumab-trastuzumab, or pertuzumab-docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial.Â©2014 American Association for Cancer Research.
FDA approval: ado-trastuzumab emtansine for the treatment of patients with HER2-positive metastatic breast cancer. - Clinical cancer research : an official journal of the American Association for Cancer Research
On February 22, 2013, the FDA licensed ado-trastuzumab emtansine (Kadcyla; Genentech, Inc.) for use as a single agent for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. The clinical basis for licensure was a phase III trial in 991 patients with HER2-positive MBC that randomly allocated patients to receive ado-trastuzumab emtansine (n=495) or lapatinib in combination with capecitabine (n=496). The coprimary endpoints were progression-free survival (PFS) based on tumor assessments by an independent review committee and overall survival (OS). Statistically significant improvements in PFS and OS were observed in patients receiving ado-trastuzumab emtansine compared with patients receiving lapatinib plus capecitabine [difference in PFS medians of 3.2 months, HR, 0.65 (95% confidence interval, CI, 0.55-0.77), P<0.0001 and difference in OS medians of 5.8 months, HR, 0.68 (95% CI, 0.55-0.85), P=0.0006]. The most common adverse reactions in patients receiving ado-trastuzumab emtansine were fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache, increased aminotransferase levels, and constipation. Other significant adverse reactions included hepatobiliary disorders and left ventricular dysfunction. Given the PFS and OS results, the benefit-risk profile was considered favorable.Â©2014 American Association for Cancer Research.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. - Lancet (London, England)
Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS.We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response--ypT0 ypN0, ypT0/is ypN0, and ypT0/is--for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS.We obtained data from 12 identified international trials and 11â€ˆ955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0Â·44, 95% CI 0Â·39-0Â·51; ypT0/is ypN0: 0Â·48, 0Â·43-0Â·54) and OS (0Â·36, 0Â·30-0Â·44; 0Â·36, 0Â·31-0Â·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0Â·60, 95% CI 0Â·55-0Â·66; OS 0Â·51, 0Â·45-0Â·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0Â·24, 95% CI 0Â·18-0Â·33; OS: 0Â·16, 0Â·11-0Â·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0Â·15, 0Â·09-0Â·27; OS: 0Â·08, 0Â·03, 0Â·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0Â·03, 95% CI 0Â·00-0Â·25) and OS (R(2)=0Â·24, 0Â·00-0Â·70).Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.US Food and Drug Administration.Copyright Â© 2014 Elsevier Ltd. All rights reserved.
First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. - Clinical cancer research : an official journal of the American Association for Cancer Research
On June 8, 2012, the U.S. Food and Drug Administration (FDA) approved pertuzumab (Perjeta, Genentech) for use in combination with trastuzumab (Herceptin, Genentech) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 808 patients with HER2-positive MBC. Patients were randomized (1:1) to receive pertuzumab (n = 402) or placebo (n = 406) in combination with trastuzumab and docetaxel. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). A statistically significant improvement in PFS (difference in medians of 6.1 months) was observed in patients receiving pertuzumab [HR, 0.62; 95% confidence interval (CI), 0.51-0.75; P < 0.0001]. A planned interim analysis suggested an improvement in OS (HR, 0.64; 95% CI, 0.47-0.88; P = 0.0053) but the HR and P value did not cross the stopping boundary. Common adverse reactions (>30%) observed in patients on the pertuzumab arm included diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. No additive cardiac toxicity was observed. Significant manufacturing issues were identified during the review. On the basis of substantial evidence of efficacy for pertuzumab in MBC and the compelling public health need, FDA did not delay availability to patients pending final resolution of all manufacturing concerns. Therefore, FDA approved pertuzumab but limited its approval to lots not affected by manufacturing problems. The applicant agreed to multiple manufacturing and testing postmarketing commitments under third-party oversight to resolve manufacturing issues.Â©2013 AACR.
FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. - The oncologist
On May 20, 2011, the U.S. Food and Drug Administration (FDA) approved sunitinib malate capsules (SutentÂ®; Pfizer, Inc., New York) for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable locally advanced or metastatic disease. In a phase III randomized trial, 171 patients received either sunitinib (37.5 mg) or placebo once daily. The progression-free survival (PFS) interval was the primary efficacy endpoint. Secondary endpoints included the overall survival (OS) time, objective response rate (ORR), patient-reported outcomes, and safety. Based on early results favoring sunitinib, the independent data monitoring committee recommended trial termination prior to the prespecified interim analysis. This premature analysis may have led to an overestimate of the treatment effect. In the FDA analysis of investigator-assessed PFS times, the median values for the sunitinib and placebo arms were 10.2 months and 5.4 months, respectively. The ORRs were 9.3% and 0% in the sunitinib and placebo arms, respectively. The OS data were not mature at the time of approval and were confounded by 69% crossover. Common adverse reactions in patients receiving sunitinib included diarrhea, nausea, asthenia, fatigue, neutropenia, hypertension, and palmar-plantar erythrodysesthesia syndrome. Two patients on sunitinib died as a result of cardiac failure. The Oncologic Drugs Advisory Committee voted eight to two that, despite residual uncertainty about the magnitude of the PFS effect because of early trial termination, sunitinib demonstrated a favorable benefit-risk profile in pNET patients. The FDA concurred with the committee's assessment and granted sunitinib regular approval for this rare malignancy with few available therapies.
Overestimation of the effect size in group sequential trials. - Clinical cancer research : an official journal of the American Association for Cancer Research
Group sequential designs (GSD), which provide for interim monitoring of efficacy data and allow potential early trial termination while preserving the type I error rate, have become commonplace in oncology clinical trials. Although ethically appealing, GSDs tend to overestimate the true treatment effect size at early interim analyses. Overestimation of the treatment effect may exaggerate the benefit of a drug and provide imprecise information for physicians and their patients about a drug's true effect. The cause and effect of such a phenomenon are generally not well understood by many in clinical trial practice. In this article, we provide a graphical explanation for why the phenomenon of overestimation in GSDs occurs. The potential overestimation of the magnitude of the treatment effect is of particular concern in oncology, in which the more subjective endpoint of progression-free survival has increasingly been adopted as the primary endpoint in pivotal phase III trials.Â©2012 AACR.
Approval summary: pemetrexed maintenance therapy of advanced/metastatic nonsquamous, non-small cell lung cancer (NSCLC). - The oncologist
On July 2, 2009, the U.S. Food and Drug Administration approved pemetrexed injection (AlimtaÂ® Injection; Eli Lilly and Company, Indianapolis, IN) for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer whose disease has not progressed after four cycles of platinum-based doublet induction chemotherapy. A double-blind study of pemetrexed plus best supportive care versus placebo plus best supportive care was conducted. Pemetrexed, 500 mg/m(2) i.v., was administered every 21 days until disease progression. Folic acid, vitamin B(12), and a corticosteroid were given to all study patients. There were 663 randomized patients (pemetrexed, 441; placebo, 222). Treatments were well balanced with respect to baseline disease characteristics and stratification factors. The median overall survival (OS) time for intent-to-treat (ITT) patients was 13.4 months for patients receiving pemetrexed and 10.6 months for those receiving placebo (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95; p = .012). Median OS times were 15.5 months versus 10.3 months for patients with nonsquamous histologies receiving pemetrexed and placebo, respectively (HR, 0.70; 95% CI, 0.56-0.88). The median OS time in patients with squamous histology receiving pemetrexed was 9.9 months, versus 10.8 months for those receiving placebo (HR, 1.07; 95% CI, 0.77-1.50). A significantly longer progression-free survival interval for both the ITT and nonsquamous patient populations receiving pemetrexed maintenance therapy was also observed. The most common (>5%) adverse reactions in patients receiving pemetrexed were hematologic toxicity, an increase in hepatic enzymes, fatigue, gastrointestinal toxicity, sensory neuropathy, and skin rash.
Approval summary: imatinib mesylate in the adjuvant treatment of malignant gastrointestinal stromal tumors. - The oncologist
On December 19, 2008, the U.S. Food and Drug Administration approved imatinib mesylate tablets for oral use (Gleevec(R); Novartis Pharmaceuticals Corporation, East Hanover, NJ) for the adjuvant treatment of adult patients following complete gross resection of Kit(+) (CD117(+)) gastrointestinal stromal tumor (GIST). A randomized, double-blind, placebo-controlled study enrolling 713 patients was submitted. The primary objective of the clinical trial was to compare the recurrence-free survival (RFS) intervals of the two groups. Overall survival (OS) was a secondary endpoint. Eligible patients were > or =18 years of age with a histological diagnosis of GIST (Kit(+)), resected tumor size > or =3 cm, and a complete gross resection within 14-70 days prior to registration. Imatinib, 400 mg orally, was administered once daily for 1 year. The study was terminated after completion of the third protocol-specified interim analysis. At that time, 100 RFS events were confirmed by a blinded central independent review. With a median follow-up of 14 months, 30 RFS events were observed in the imatinib group and 70 were observed in the placebo group (hazard ratio, 0.398; 95% confidence interval, 0.259-0.610; two-sided p-value < .0001). OS results are immature. Most patients in both groups experienced at least one adverse reaction, and 31% of the imatinib group and 18% of the placebo group experienced grade > or =3 adverse reactions. The most frequently reported adverse reactions (> or =20%) were diarrhea, fatigue, nausea, edema, decreased hemoglobin, rash, vomiting, and abdominal pain. Drug was discontinued for adverse reactions in 17% and 3% of the imatinib and placebo-treated patients, respectively.
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