Dr Rebecca Kristeleit

Oncologist, Consultant Medical Oncologist, University College London Hospitals
  • London, United Kingdom
  • En, En
  • Best at: Gynaecological cancers

Dr Rebecca Kristeleit is Clinical Senior Lecturer and Consultant Medical Oncologist at UCL/UCLH. She specialises in the treatment of gynaecological cancers: Cervical cancer, Endometrial cancer, Ovarian cancer. She also has a specialist interest in drug development as well and is leading several clinical trials of novel agents relevant to gynecological malignancies including PARP inhibitors. Rebecca qualified in medicine from St Andrew’s and Manchester Universities including eight months at the University of Lausanne (Switzerland) on an Erasmus scholarship. Following general medical training in London, Rebecca undertook her medical oncology training at The Royal Marsden Hospital and a CRUK-funded research fellowship at the Institute of Cancer Research. Subsequently, Rebecca spent a year as a senior research fellow on the Drug Development Unit at the Royal Marsden Hospital gaining specialist experience in the design and conduct of early phase clinical trials and translational medicine. She is Principle Investigator for trials for women with gynaecological cancers at both UCLH and the Sarah Cannon Research Institute (SCRI) UK. Her research work is focused on the development of early phase clinical trials and translational research to identify and evaluate innovative treatment strategies for gynecological malignancies as well as other solid tumours. She is a current member of the ASCO Scientific Programme Committee, NCRI endometrial sub-group committee and is the Research Lead for gynaecological cancers in the North Thames Cancer Research Network.She has given a number of national and international talks at conferences including ASCO, ESMO and BGCS.

Statistics.

Achievements of Dr Rebecca Kristeleit

Trustedoctor credentials
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Clinical endorsements
23
Articles
224
Scientific
co-authors
Trustedoctor credentials
7
General specialty
9
Subspeciality
Languages

About.

Information about Dr Rebecca Kristeleit

Timeline
Place
Country
Position
Focus
St Andrew’s and Manchester Universities
United Kingdom
MBBS
Medicine
Timeline
Place
Country
Position
Focus
Since 2009
University College London Hospitals
United Kingdom
Consultant Medical Oncologist
Gynaecological cancers
Since 2009
University College London Hospitals
United Kingdom
Clinical Senior Lecturer
Experimental therapeutics
2008-2009
Drug Development Unit Royal Marsden
United Kingdom
Senior Clinical Research Fellowship
Drug Development Research
2001-2008
Drug Development Unit Royal Marsden
United Kingdom
Specialist Registrar and CRUK Clinical Research Fellow
Medical Oncology
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Organization
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Clinical Experience.

General speciality (7)
Patients per year
Patients total
metastasis-cervical cancer
0-50
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cervical cancer
0-100
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ovarian cancer
0-100
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general gynaecological oncology
0-100
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chemotherapy
0-50
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targeted therapy
0-50
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immunotherapy
0-50
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Tumor speciality (9)
Patients per year
Patients total
high-grade serous ovarian carcinoma
0-50
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sarcoma of cervix
0-50
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lymphoma of cervix
0-50
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adenocarcinoma of cervix
0-50
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mucinous ovarian carcinoma
0-50
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high-grade serous ovarian carcinoma
0-50
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endometrioid ovarian carcinoma
0-50
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endometrioid adenocarcinoma
0-50
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clear cell uterine carcinoma
0-50
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Skills & Endorsements.

General specialty
targeted therapy
immunotherapy
chemotherapy
general gynaecological oncology

Academic research.

23
Total articles
  • chemotherapy - 20
  • radiotherapy - 1
  • surgery - 2
23
gynaecological cancer articles - Impact Factor
  • gynaecological cancer - 23
  • oncology therapy - 23
Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2.

An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC).

Enumeration and Molecular Characterisation of Circulating Tumour Cells in Endometrial Cancer.

This is a feasibility study to determine whether circulating tumour cells (CTCs) are detectable and suitable for molecular profiling in advanced endometrial cancer (aEC).

A phase I pharmacokinetic and pharmacodynamic study of CHR-3996, an oral class I selective histone deacetylase inhibitor in refractory solid tumors.

This clinical trial investigated the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of CHR-3996, a selective class I histone deacetylase inhibitor.

A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer.

Indoleamine 2,3-dioxygenase-1 (IDO1) is a key regulator of immune tolerance in ovarian cancer. This study investigated efficacy and safety of the IDO1 enzyme inhibitor epacadostat versus tamoxifen in patients with biochemical-only recurrence (CA-125 elevation) following complete remission after first-line chemotherapy for advanced epithelial ovarian, primary peritoneal, or fallopian tube cancer.

Clinical factors of response in patients with advanced ovarian cancer participating in early phase clinical trials.

Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.

A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline -Mutated Ovarian Carcinoma or Other Solid Tumors.

Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate single-agent oral rucaparib at multiple doses. Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1. In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline -mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression). Rucaparib was tolerable and had activity in patients with platinum-sensitive germline -mutated HGOC. .

ENGOT-ov-6/TRINOVA-2: Randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer.

Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomised, double-blind, placebo-controlled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer.

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial.

Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor.

A phase I study of afatinib combined with paclitaxel and bevacizumab in patients with advanced solid tumors.

The combination of afatinib, an irreversible ErbB family blocker, with paclitaxel and bevacizumab was assessed in patients with advanced solid tumors.

Outcome of patients with advanced ovarian cancer who do not undergo debulking surgery: A single institution retrospective review.

To assess the outcome of patients with advanced ovarian cancer (OC) who were treated without surgery, having received upfront chemotherapy and no interval debulking surgery (IDS).

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies.

The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses.

Gynecologic Cancers: Emerging Novel Strategies for Targeting DNA Repair Deficiency.

The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed "BRCAness"). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined. They include individual gene defects (e.g., RAD51 mutation, CHEK2 mutation), homozygous somatic loss, and whole genome properties such as genomic scarring. Testing this knowledge is possible when selecting patients to receive molecular therapy targeting DNA repair, not only for patients with ovarian cancer but also endometrial and cervical cancers. The validity of HRD assays and multiple gene sequencing panels to select a broader population of patients for treatment with PARP inhibitor therapy is under evaluation. Other non-HRD targets for exploiting DNA repair defects in gynecologic cancers include mismatch repair (MMR), checkpoint signaling, and nonhomologous end-joining (NHEJ) DNA repair. This article describes recent evidence supporting strategies in addition to BRCA mutation for selecting patients for treatment with PARP inhibitor therapy. Additionally, the challenges and opportunities of exploiting DNA repair pathways other than homologous recombination for molecular therapy in gynecologic cancers is discussed.

Phase I pharmacokinetic and pharmacodynamic study of LAQ824, a hydroxamate histone deacetylase inhibitor with a heat shock protein-90 inhibitory profile, in patients with advanced solid tumors.

To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy.

Homologous recombination deficiency and ovarian cancer.

The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer. Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation.

Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study.

Activating FGFR2 mutations are found in 10-16% of primary endometrial cancers and provide an opportunity for targeted therapy. We assessed the safety and activity of dovitinib, a potent tyrosine-kinase inhibitor of fibroblast growth factor receptors, VEGF receptors, PDGFR-β, and c-KIT, as second-line therapy both in patients with FGFR2-mutated (FGFR2(mut)) endometrial cancer and in those with FGFR2-non-mutated (FGFR2(non-mut)) endometrial cancer.

First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.

This first-in-human dose-escalation trial evaluated the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity of pictilisib (GDC-0941), an oral, potent, and selective inhibitor of the class I phosphatidylinositol-3-kinases (PI3K).

An inflammation based score can optimize the selection of patients with advanced cancer considered for early phase clinical trials.

Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR).

Developing an objective marker to optimize patient selection and predict survival benefit in early-phase cancer trials.

Several prognostic indices have been devised to optimize patient selection for phase 1 oncology trials with no consensus as to the optimal score and none qualifying as a marker of treatment response.

First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.

This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors.

A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi).

Treatment with olaparib in a patient with PTEN-deficient endometrioid endometrial cancer.

A 58-year-old woman presented with metastatic endometrioid endometrial adenocarcinoma after being previously treated with surgery and adjuvant radiotherapy for early-stage endometrial cancer. She had received several lines of chemotherapy for multiple relapses over 9 years and displayed a profound sensitivity to platinum-containing regimens.

Early oncology clinical trial design in the era of molecular-targeted agents.

The introduction of molecularly targeted agents has changed the concept of drug development. The field has evolved over the last decade and therapeutic drugs are now being rationally designed to affect specific intracellular or extracellular pathways that are thought to be important for cancer progression. Traditionally, toxicity has been the primary end point for dose definition and escalation; however, novel targeted compounds are characterized by the lack of significant clinical toxicity compared with conventional chemotherapy. Alternative trial designs and pharmacodynamic-driven biomarkers that assess drug-target effect and allow demonstration of proof-of-concept for intended target modulation and achievement of desired biological effects have emerged to guide dose selection. This must be facilitated by validated preclinical tumor models and biomarker assays that are critical to aid understanding of which agents are likely to be beneficial in different cancer subtype patients and which biomarkers should be implemented into early trial design.

Emerging promise of epigenetics and DNA methylation for the diagnosis and management of women's cancers.

Over the last two decades, survival rates from women's cancers (breast, ovarian, endometrial and cervical cancer) have all but modestly improved despite huge efforts from both research and clinical communities. In parallel with this, the field of epigenetics has grown from its infancy into a promising scientific discipline. In particular, DNA methylation analysis has been adopted by oncologists in an attempt to better understand and manage cancer. Now that the epigenetic technological base has caught up, the potential of methylation markers in cancer research is finally being realized. In this review, we present the current status of epigenetic research into women's cancers with a main focus on DNA methylation analysis. We provide an overview of technological development, current markers of risk prediction, early detection, diagnosis, prognosis and response to treatment, and highlight the progression of epigenetic therapies. Finally, we comment on the potential impact of epigenetic analyses on the future of women's health.

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224
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