Clinical Focus

  • Oncology

Academic Appointments

Administrative Appointments

  • Director, Phase I Clinical Research Program, Division of Oncology, Stanford School of Medicine (2015 - Present)
  • Professor of Medicine, Department of Medicine (2015 - Present)

Professional Education

  • Medical Education:Lady Hardinge Medical College (1992) India
  • Residency:Emory University Internal Medicine Primary Care ResidencyGA
  • Fellowship:National Institutes of HealthMD
  • Board Certification: Oncology, American Board of Internal Medicine (1998)
  • Internship:Emory University School of MedicineGA

Research & Scholarship

Current Research and Scholarly Interests

Dr. Kummar’s research interests focus on developing novel therapies for cancer. She specializes in conducting pharmacokinetic and pharmacodynamic driven first-in-human trials tailored to make early, informed decisions regarding the suitability of novel molecular agents for further clinical investigation. Her studies integrate genomics and laboratory correlates into early phase trials. She is interested in alternate trial designs to facilitate rational drug selection based on human data and help expedite drug development timelines. She has published numerous articles in medical journals and serves on a number of national and international scientific committees.

Clinical Trials

  • Study of Cabiralizumab in Patients With Pigmented Villonodular Synovitis / Diffuse Type Tenosynovial Giant Cell Tumor Not Recruiting

    This is a phase 1/2 single arm, open-label, safety, tolerability, and PK study of Cabiralizumab in PVNS/dt-TGCT patients. Patients will be enrolled into either Phase 1 (dose escalation) or Phase 2 (dose expansion) of the study, but not both.

    Stanford is currently not accepting patients for this trial. For more information, please contact Maria Ahern, 650-725-6413.

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  • JTX-2011 Alone and in Combination With Anti-PD-1 or Anti-CTLA-4 in Subjects With Advanced and/or Refractory Solid Tumors Recruiting

    JTX-2011-101 is a Phase 1/2, open label, dose escalation and expansion clinical study of JTX-2011 alone and in combination with nivolumab, ipilimumab, or pembrolizumab in adult subjects with advanced and/or refractory solid tumors, to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), as well as to evaluate preliminary efficacy.

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  • An Investigational Immuno-therapy Study to Determine the Safety of Urelumab Given in Combination With Nivolumab in Solid Tumors and B-cell Non-Hodgkin's Lymphoma Not Recruiting

    The purpose of this study is to determine which doses of Urelumab and Nivolumab are safe and tolerable when they are given together.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kristine McGlennen, 650-723-3589.

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  • Trial of CMB305 and Atezolizumab in Patients With Sarcoma Not Recruiting

    This is an open-label Phase 2 randomized study that will examine the use of the study agents, CMB305 (sequentially administered LV305 [a dendritic cell-targeting viral vector expressing the NY-ESO-1 gene] and G305 [NY-ESO-1 recombinant protein plus GLA-SE]) in combination with atezolizumab or atezolizumab alone, in patients with locally advanced, relapsed or metastatic sarcoma (synovial or myxoid/round cell liposarcoma) expressing the NY-ESO-1 protein. CMB305 is a novel approach designed to stimulate the body's immune system to fight the spread and growth of cancer in patients whose tumors express the NY-ESO-1 protein. LV305 will be given in a prime-boost approach with G305 to induce a potentially synergistic immunotherapeutic response in combination with atezolizumab.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Phase 2 Study of ABI-009 in Patients With Advanced Malignant PEComa Recruiting

    A phase 2 multi-center investigation of efficacy of ABI-009 (nab-rapamycin) in patients with advanced malignant perivascular epithelioid cell tumor (PEComa)

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  • A Study of PLX8394 as a Single Agent in Patients With Advanced Unresectable Solid Tumors Not Recruiting

    The objective of this study is to determine the safety, pharmacokinetics, maximum tolerated dose/recommended Phase 2 dose, and efficacy of PLX8394.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Phase III Trial of Anlotinib in Metastatic or Advanced Alveolar Soft Part Sarcoma, Leiomyosarcoma and Synovial Sarcoma Recruiting

    This study evaluates the safety and efficacy of AL3818 (anlotinib) hydrochloride in the treatment of metastatic or advanced alveolar soft part sarcoma (ASPS), leiomyosarcoma (LMS), and synovial sarcoma (SS). All participants with ASPS will receive open-label AL3818. In participants with LMS or SS, AL3818 will be compared to IV dacarbazine. Two-thirds of the participants will receive AL3818, one-third of the participants will receive IV dacarbazine.

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  • VX-970 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery Not Recruiting

    This phase I trial studies the side effects and best dose of ATR kinase inhibitor M6620 (VX-970) and irinotecan hydrochloride in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or cannot be removed by surgery. VX-970 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

    Stanford is currently not accepting patients for this trial. For more information, please contact Shivaani Kummar, 800-411-1222.

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  • A Trial of Intratumoral Injections of SD-101 in Combination With Pembrolizumab in Patients With Metastatic Melanoma or Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Recruiting

    This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, tolerability, biologic activity, and preliminary efficacy of intratumoral SD 101 injections in combination with intravenous pembrolizumab in patients with metastatic melanoma or recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Phase 1 of this trial is a modified 3+3 dose escalation study evaluating escalating or intermediate dose levels of SD-101 given with a fixed dose of pembrolizumab in patients with metastatic melanoma. Phase 2 of this study will consist of 7 expansion cohorts to further evaluate the efficacy and safety of SD-101 given in combination with pembrolizumab in specific melanoma and HNSCC populations: For each of the indications in melanoma and HNSCC 2 separate cohorts will be recruited, those who are anti-programmed death receptor-1/ligand 1 (anti-PD-1/L1) therapy naïve and those who have progressive disease (PD) while receiving anti-PD-1/L1 therapy.

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  • Safety Study of MGD009 in B7-H3-expressing Tumors Recruiting

    The purpose of this study is to evaluate the safety of MGD009 when given to patients with B7-H3-expressing tumors. The study will also evaluate what is the highest dose of MGD009 that can be given safely. Assessments will be done to see how the drug acts in the body (pharmacokinetics (PK), pharmacodynamics (PD) and to evaluate potential anti-tumor activity of MGD009.

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  • Phase 1/1b Study to Evaluate the Safety and Tolerability of CPI-444 Alone and in Combination With Atezolizumab in Advanced Cancers Recruiting

    This is a phase 1/1b open-label, multicenter, dose-selection study of CPI-444, an oral small molecule targeting the adenosine-A2A receptor on T-lymphocytes and other cells of the immune system. This trial will study the safety, tolerability, and anti-tumor activity of CPI-444 as a single agent and in combination with atezolizumab, a PD-L1 inhibitor against various solid tumors. CPI-444 blocks adenosine from binding to the A2A receptor. Adenosine suppresses the anti-tumor activity of T cells and other immune cells.

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  • Phase 1/2 Study of LOXO-195 in Patients With Previously Treated NTRK Fusion Cancers Recruiting

    This is a Phase 1/2, multi-center, open-label study designed to evaluate the safety and efficacy of LOXO-195 when administered orally to patients age ≥ 1 month and older with NTRK fusion cancers treated with a prior TRK inhibitor.

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  • Study of the Safety, Pharmacokinetics and Efficacy of EDO-S101, in Patients With Advanced Solid Tumors Recruiting

    Tinostamustine (EDO-S101) is a new chemical entity, an AK-DAC (a first-in-class alkylating deacetylase inhibiting molecule) that, in preclinical studies, has been shown to simultaneously improve access to the DNA strands within cancer cells, break them and block damage repair. This Phase 1/2 study will enroll patients with various advanced solid tumors.

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  • Study of ADCT-502 in Patients With Advanced Solid Tumors With HER2 Expression Not Recruiting

    This study evaluates ADCT-502 in patients with Advanced Solid Tumors with HER2 Expression. Patients will participate in a dose-escalation phase (Part 1) and dose expansion (Part 2). In Part 2, patients will receive the dose level identified in Part 1.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Study of LOXO-101 (Larotrectinib) in Subjects With NTRK Fusion Positive Solid Tumors (NAVIGATE) Recruiting

    Phase II, multi-center, open-label study of patients with advanced solid tumors harboring a fusion of NTRK1, NTRK2 or NTRK3.

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  • A Study Of PF-06647020 For Adult Patients With Advanced Solid Tumors Recruiting

    To assess the safety and tolerability at increasing dose levels of PF-06647020 in patients with advanced solid tumors in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.

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2018-19 Courses


All Publications

  • Biodistribution, tumor detection and radiation dosimetry of F-18 5-Fluoro-2'-Deoxycytidine (18F-FdCyd) with Tetrahydrouridine in solid tumors. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Young, C. R., Adler, S., Eary, J. F., Lindenberg, M. L., Jacobs, P. M., Collins, J., Kummar, S., Kurdziel, K. A., Choyke, P. L., Mena, E. 2018


    In pre-clinical studies, 5-fluoro-2'-deoxycytidine (FdCyd), an inhibitor of DNA methyltransferase and DNA hypermethylation, has shown treatment efficacy against multiple malignancies by suppressing epigenetic hypermethylation in tumor cells. Several clinical trials are undergoing using FdCyd and while some patients may respond to this drug, in the majority of patients it is ineffective. Thus, by establishing a non-invasive imaging modality to evaluate the distribution of the drug may provide insight into the variable responses. Objective: A novel experimental radiopharmaceutical, Fluorine-18 labeled FdCyd (18F-FdCyd), was developed as a companion imaging agent to the non-radioactive form of the drug, FdCyd. We present the first-in human radiation dosimetry results and biodistribution of 18F-FdCyd, administered along with tetrahydrouridine, an inhibitor of cytidine/deoxycytidine deaminase, in patients with a variety of solid tumors undergoing FdCyd therapy. Methods: This phase 0 imaging trial examined the 18F-FdCyd biodistribution and radiation dosimetry in 5 human subjects enrolled in companion therapy trials. In each subject, four sequential PET scans were acquired to estimate whole body and individual organ effective dose, using OLINDA/EXM v1.0. Tumor to background (T:B) ratios were also calculated for the tumor sites visualized on PET/CT imaging. Results: Average whole body effective dose for the experimental radiopharmaceutical 18F-FdCyd administered in conjunction with tetrahydrouridine was 2.12E-02 ± 4.15E-03 mSv/MBq. This is similar to the radiation dose estimates for 18F-FDG PET. The critical organ, with the highest absorbed radiation dose was the urinary bladder wall at 7.96E-02 mSv/MBq. Other organ doses of note were the liver (6.02E-02mSv/MBq), kidneys (5.26E-02 mSv/MBq), and gallbladder (4.05E-02 mSv/MBq). Tumor target to background ratios ranged from 2.4 to 1.4, which potentially enable tumor visualization in static PET images. Conclusion: This phase 0 imaging clinical trial provides evidence that 18F-FdCyd administered in conjunction with tetrahydrouridine yields acceptable individual organ and whole body effective doses, as well as modest T:B ratios that potentially enable tumor visualization. Dose estimates for 18F-FdCyd are comparable to those of other PET radiopharmaceuticals such as 18F-FDG. Further studies with larger study population are warranted to assess 18F-FdCyd imaging as a predictor of FdCyd treatment effectiveness.

    View details for DOI 10.2967/jnumed.118.216994

    View details for PubMedID 30389817

  • TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Targeted oncology Kummar, S., Lassen, U. N. 2018


    Oncogenic somatic chromosomal rearrangements involving the NTRK1, NTRK2 or NTRK3 genes (NTRK gene fusions) occur in up to 1% of all solid tumors, and have been reported across a wide range of tumor types. The fusion proteins encoded by such rearranged sequences have constitutively activated TRK tyrosine kinase domains, providing novel therapeutic anticancer targets. The potential clinical effectiveness of TRK inhibition in patients with tumors harboring NTRK gene fusions is being assessed in phase I and II trials of TRK inhibitors, such as larotrectinib and entrectinib. Clinical trial results have demonstrated that larotrectinib is generally well tolerated and has shown high response rates that are durable across tumor types. These data validate NTRK gene fusions as actionable genomic alterations. In this review, we present the clinical data, discuss the different approaches that might be used to routinely screen tumors to indicate the presence of NTRK gene fusions, explore the issue of acquired resistance to TRK inhibition, and reflect on the wider regulatory considerations for tumor site agnostic TRK inhibitor drug development.

    View details for DOI 10.1007/s11523-018-0590-1

    View details for PubMedID 30276762

  • SD-101 in Combination with Pembrolizumab in Advanced Melanoma: Results of a Phase Ib, Multicenter Study CANCER DISCOVERY Ribas, A., Medina, T., Kummar, S., Amin, A., Kalbasi, A., Drabick, J. J., Barve, M., Daniels, G. A., Wong, D. J., Schmidt, E., Candia, A. F., Coffmanm, R. L., Leung, A. F., Janssen, R. S. 2018; 8 (10): 1250–57


    PD-1 inhibitors are approved for treating advanced melanoma, but resistance has been observed. This phase Ib trial evaluated intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9), in combination with pembrolizumab in patients with unresectable or metastatic malignant melanoma. The most common adverse events related to SD-101 were injection-site reactions and transient, mild-to-moderate "flu-like" symptoms. Among the 9 patients naïve to anti-PD-1 therapy, the overall response rate (ORR) was 78%. The estimated 12-month progression-free survival rate was 88%, and the overall survival rate was 89%. Among 13 patients having prior anti-PD-1 therapy, the ORR was 15%. RNA profiling of tumor biopsies demonstrated increased CD8+ T cells, natural killer cells, cytotoxic cells, dendritic cells, and B cells. The combination of intratumoral SD-101 and pembrolizumab was well tolerated and induced broad immune activation in the tumor microenvironment with durable tumor responses in both peripheral and visceral lesions.Significance: These early data demonstrate that the combination of pembrolizumab with intratumoral SD-101 is well tolerated and can induce immune activation at the tumor site. Combining an intratumoral TLR9 innate immune stimulant with PD-1 blockade can potentially increase clinical efficacy with minimal additional toxicity relative to PD-1 blockade alone. Cancer Discov; 8(10); 1250-7. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1195.

    View details for DOI 10.1158/2159-8290.CD-18-0280

    View details for Web of Science ID 000446398800007

    View details for PubMedID 30154193

  • First-in-human study of the epichaperome inhibitor PU-H71: clinical results and metabolic profile INVESTIGATIONAL NEW DRUGS Speranza, G., Anderson, L., Chen, A. P., Khanh Do, Eugeni, M., Weil, M., Rubinstein, L., Majerova, E., Collins, J., Horneffer, Y., Juwara, L., Zlott, J., Bishop, R., Conley, B. A., Streicher, H., Tomaszewski, J., Doroshow, J. H., Kummar, S. 2018; 36 (2): 230–39


    Background Molecular chaperone targeting has shown promise as a therapeutic approach in human cancers of various histologies and genetic backgrounds. The purine-scaffold inhibitor PU-H71 (NSC 750424), selective for Hsp90 in epichaperome networks, has demonstrated antitumor activity in multiple preclinical cancer models. The present study was a first in-human trial of PU-H71 aimed at establishing its safety and tolerability and characterizing its pharmacokinetic (PK) profile on a weekly administration schedule in human subjects with solid tumors refractory to standard treatments. Methods PU-H71 was administered intravenously over 1 h on days 1 and 8 of 21-day cycles in patients with refractory solid tumors. Dose escalation followed a modified accelerated design. Blood and urine were collected during cycles 1 and 2 for pharmacokinetics analysis. Results Seventeen patients were enrolled in this trial. Grade 2 and 3 adverse events were observed but no dose limiting toxicities occurred, thus the human maximum tolerated dose was not determined. The mean terminal half-life (T1/2) was 8.4 ± 3.6 h, with no dependency to dose level. A pathway for the metabolic disposal of PU-H71 in humans was derived from microsome studies. Fourteen patients were also evaluable for clinical response; 6 (35%) achieved a best response of stable disease for >2 cycles, with 2 patients remaining on study for 6 cycles. The study closed prematurely due to discontinuation of drug supply. Conclusions PU-H71 was well tolerated at the doses administered during this study (10 to 470 mg/m2/day), with no dose limiting toxicities.

    View details for DOI 10.1007/s10637-017-0495-3

    View details for Web of Science ID 000428433500006

    View details for PubMedID 28808818

  • The evolving paradigm of cancer trials NATURE REVIEWS DRUG DISCOVERY Kummar, S. 2018; 17 (4): 225–26

    View details for DOI 10.1038/nrd.2017.210

    View details for Web of Science ID 000428524100001

    View details for PubMedID 29269944

  • Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children NEW ENGLAND JOURNAL OF MEDICINE Drilon, A., Laetsch, T. W., Kummar, S., DuBois, S. G., Lassen, U. N., Demetri, G. D., Nathenson, M., Doebele, R. C., Farago, A. F., Pappo, A. S., Turpin, B., Dowlati, A., Brose, M. S., Mascarenhas, L., Federman, N., Berlin, J., El-Deiry, W. S., Baik, C., Deeken, J., Boni, V., Nagasubramanian, R., Taylor, M., Rudzinski, E. R., Meric-Bernstam, F., Sohal, D. S., Ma, P. C., Raez, L. E., Hechtman, J. F., Benayed, R., Ladanyi, M., Tuch, B. B., Ebata, K., Cruickshank, S., Ku, N. C., Cox, M. C., Hawkins, D. S., Hong, D. S., Hyman, D. M. 2018; 378 (8): 731–39


    Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions.We enrolled patients with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events.Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; numbers, NCT02122913 , NCT02637687 , and NCT02576431 .).

    View details for DOI 10.1056/NEJMoa1714448

    View details for Web of Science ID 000425613900010

    View details for PubMedID 29466156

    View details for PubMedCentralID PMC5857389

  • Cold agglutinin disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care utilization BLOOD ADVANCES Mullins, M., Jiang, X., Bylsma, L. C., Fryzek, J. P., Reichert, H., Chen, E. C., Kummar, S., Rosenthal, A. 2017; 1 (13): 839–48


    Cold agglutinin disease (CAD), a rare disease and subtype of autoimmune hemolytic anemia, is characterized by autoantibodies that bind to red blood cells at low temperatures. There is no established standard of care for CAD treatment and CAD cohort studies are limited by the rarity of the condition. The objectives of this study are to present the longitudinal experience of a CAD cohort from the United States, with a focus on anemia severity, use of medications and transfusions, and health care resource utilization. The Stanford Translational Research Integrated Database Environment database was used to retrospectively identify CAD patients diagnosed and treated at Stanford Health Care from 2000 to 2016. Twenty-nine patients were included in this analysis. There were 7.1 severe anemia events per patient-year observed over the follow-up time. For CAD patients treated at Stanford, there was a mean of 3.5 therapies per patient. Transfusions were given in at least 65% of the cohort with a mean of 11 transfusions per patient-year. For CAD-related health care use in the first year after disease onset, 93% used outpatient services with a median of 26 outpatient visits per patient. The data presented here likely represent the minimum number of events for these patients during this timeframe, as this single-center experience does not capture care from other providers. This longitudinal study of CAD patients demonstrates the severity of anemia and relapsing nature of the disease, even after administration of multiple therapies and transfusions.

    View details for DOI 10.1182/bloodadvances.2017004390

    View details for Web of Science ID 000401894800006

    View details for PubMedID 29296728

    View details for PubMedCentralID PMC5727809

  • A phase 2 study of vorinostat in locally advanced, recurrent, or metastatic adenoid cystic carcinoma. Oncotarget Goncalves, P. H., Heilbrun, L. K., Barrett, M. T., Kummar, S., Hansen, A. R., Siu, L. L., Piekarz, R. L., Sukari, A. W., Chao, J., Pilat, M. J., Smith, D. W., Casetta, L., Boerner, S. A., Chen, A., Lenkiewicz, E., Malasi, S., LoRusso, P. M. 2017; 8 (20): 32918-32929


    Vorinostat is a histone deacetylase inhibitor (HDACi). Based on a confirmed partial response (PR) in an adenoid cystic carcinoma (ACC) patient treated with vorinostat in a prior phase 1 trial, we initiated this phase 2 trial.Vorinostat was administered orally 400 mg daily, 28 day cycles. The primary objective was to evaluate response rate (RR). Exploratory studies included whole exome sequencing (WES) of selected patients.Thirty patients were enrolled. Median age of patients was 53 years (range 21-73). Median number of cycles was 5 (range 1-66). Lymphopenia (n = 5), hypertension (n = 3), oral pain (n = 2), thromboembolic events (n = 2) and fatigue (n = 2) were the only grade 3 adverse events (AEs) that occurred in more than 1 patient. Eleven patients were dose reduced secondary to drug-related AEs. Two patients had a partial response (PR), with response durations of 53 and 7.2 months. One patient had a minor response with a decrease in ascites (for 19 cycles). Stable disease was the best response in 27 patients. Targeted and WES of 8 patients in this trial identified mutations in chromatin remodeling genes highlighting the role of the epigenome in ACC.Vorinostat demonstrated efficacy in patients with ACC supporting the inclusion of HDACi in future studies to treat ACC.

    View details for DOI 10.18632/oncotarget.16464

    View details for PubMedID 28415633

  • Clinical Activity of the gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis) JOURNAL OF CLINICAL ONCOLOGY Kummar, S., Coyne, G. O., Do, K. T., Turkbey, B., Meltzer, P. S., Polley, E., Choyke, P. L., Meehan, R., Vilimas, R., Horneffer, Y., Juwara, L., Lih, A., Choudhary, A., Mitchell, S. A., Helman, L. J., Doroshow, J. H., Chen, A. P. 2017; 35 (14): 1561-?
  • Molecular insights into desmoid tumors. Oncotarget Bui, N., Kummar, S. 2017; 8 (53): 90608–9

    View details for DOI 10.18632/oncotarget.21293

    View details for PubMedID 29207578

    View details for PubMedCentralID PMC5710859

  • Evolution of early phase clinical trials in oncology. Journal of molecular medicine (Berlin, Germany) Bui, N. Q., Kummar, S. 2017


    The therapeutic armamentarium for the treatment of cancer has rapidly evolved with the advent of molecularly targeted and immuno-oncology agents. Dramatic and prolonged responses observed in patients with advanced cancers have created excitement and promise for expedited development of effective new treatments. However, this has also necessitated a rethinking of our early phase clinical trial designs and the process of optimally developing a novel agent. In this review, we discuss the current state and future directions of phase I clinical trials in oncology. Firstly, we cover the statistical methodologies behind rules and model-based dose escalation designs, and what the future holds for optimal dose selection beyond targeting the maximum tolerated dose. Next, we discuss the recent adoption of seamless expansion strategies to expedite drug development timelines, highlighted by the pembrolizumab KEYNOTE-001 trial, and potential pitfalls with this approach. Finally, we delve into the concepts behind genomic matching trials, including early success stories and the challenges that lie ahead.

    View details for DOI 10.1007/s00109-017-1612-7

    View details for PubMedID 29177698

  • The root causes of pharmacodynamic assay failure SEMINARS IN ONCOLOGY Ferry-Galow, K. V., Makhlouf, H. R., Wilsker, D. F., Lawrence, S. M., Pfister, T. D., Marrero, A. M., Bigelow, K. M., Yutzy, W. H., Ji, J. J., Butcher, D. O., Gouker, B. A., Kummar, S., Chen, A. P., Kinders, R. J., Parchment, R. E., Doroshow, J. H. 2016; 43 (4): 484-491


    Robust pharmacodynamic assay results are valuable for informing go/no-go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. This is especially true in the evaluation of pre- and post-dose tumor biopsies, which suffer from high levels of tumor insufficiency due to variations in biopsy collection techniques and significant specimen heterogeneity within and across patients. Developing methods to assess heterogeneous biopsies is necessary in order to evaluate a majority of tumor biopsies collected for pharmacodynamic biomarker studies. Improved collection devices and standardization of methods are being sought in order to improve the tumor content and quality of tumor biopsies. In terms of reagent variability, we have found that stringent initial reagent qualification and quality control of R&D-grade reagents is critical to minimize lot-to-lot variability and prevent assay failures, especially for clinical pharmacodynamic questions, which often demand assay performance that meets or exceeds clinical diagnostic assay standards. Rigorous reagent specifications and use of appropriate assay quality control methodologies help to ensure consistency between assay runs, laboratories and trials to provide much needed pharmacodynamic insights into the activity of investigational agents.

    View details for DOI 10.1053/j.seminoncol.2016.06.006

    View details for Web of Science ID 000384870100007

    View details for PubMedID 27663480

  • Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials SEMINARS IN ONCOLOGY Kummar, S., Khanh Do, K., Coyne, G. O., Chen, A., Ji, J., Rubinstein, L., Doroshow, J. H. 2016; 43 (4): 446-452


    Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early-phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. Assessing target modulation in paired tumor biopsies in patients with solid tumors presents multiple challenges, including procedural issues such as patient safety, ethical considerations, and logistics of sample handling and processing. In addition, the availability of qualified biomarker assay technologies, resources to conduct such studies, and real-time analysis of samples to detect inter-species differences that may affect the determination of optimal sampling time points must be taken into account. This article provides a discussion of the challenges that confront the practical application of pharmacodynamic studies in early-phase clinical trials of anti-cancer agents.

    View details for DOI 10.1053/j.seminoncol.2016.06.002

    View details for Web of Science ID 000384870100003

    View details for PubMedID 27663476

  • Developing therapies for rare tumors: opportunities, challenges and progress EXPERT OPINION ON ORPHAN DRUGS Bradford, D., Reilly, K. M., Widemann, B. C., Sandler, A., Kummar, S. 2016; 4 (1): 93-103
  • Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy. Current opinion in oncology O'Sullivan Coyne, G., Chen, A., Kummar, S. 2015; 27 (6): 475-481


    The article presents the rationale, clinical development, and current status of poly (ADP ribose) polymerase inhibitors (PARPis) as anticancer agents.The recent approval of olaparib in heavily pretreated patients with advanced ovarian cancer carrying a BRCA1/2 mutation represents a significant therapeutic advance for patients with this difficult to treat disease. Though olaparib is the first agent in this class to be approved, multiple PARPis are in various stages of clinical development, including in combination with other treatment modalities such as radiation, antiangiogenic agents, and cytotoxic chemotherapies.Clinical benefit has been observed with PARPis in patients with advanced BRCA1/2 mutant ovarian and breast cancers. Various PARPis, either as single agents or in combination, are being evaluated in the neoadjuvant, adjuvant, and metastatic settings.

    View details for DOI 10.1097/CCO.0000000000000238

    View details for PubMedID 26447876

  • Delivering on the promise: poly ADP ribose polymerase inhibition as targeted anticancer therapy CURRENT OPINION IN ONCOLOGY Coyne, G. O., Chen, A., Kummar, S. 2015; 27 (6): 475-481


    The article presents the rationale, clinical development, and current status of poly (ADP ribose) polymerase inhibitors (PARPis) as anticancer agents.The recent approval of olaparib in heavily pretreated patients with advanced ovarian cancer carrying a BRCA1/2 mutation represents a significant therapeutic advance for patients with this difficult to treat disease. Though olaparib is the first agent in this class to be approved, multiple PARPis are in various stages of clinical development, including in combination with other treatment modalities such as radiation, antiangiogenic agents, and cytotoxic chemotherapies.Clinical benefit has been observed with PARPis in patients with advanced BRCA1/2 mutant ovarian and breast cancers. Various PARPis, either as single agents or in combination, are being evaluated in the neoadjuvant, adjuvant, and metastatic settings.

    View details for DOI 10.1097/CCO.0000000000000238

    View details for Web of Science ID 000369624100007

    View details for PubMedCentralID PMC4636335