60 research outputs found
Funda Meric-Bernstam, MD
No full texthttps://openworks.mdanderson.org/legendsandlegacieschapters/1015/thumbnail.jp
Supplemental Data for A Phase II Study of Talazoparib Tosylate in Advanced Cancer Patients with Somatic and Germline (Not Breast or Ovarian Cancer) Alterations of BRCA1/2, Mutations/Deletions/Amplification in Other Homologous Recombination Repair Pathway Genes and PTEN or PTEN loss
No full textThe de-identified participant data and dataset generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Custom code that was used in the generation or analysis of the datasets is available upon reasonable request.
Corresponding Author: Sarina Piha-Paul,Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), University of Texas MD Anderson Cancer Center, Houston, TX. Phone: (713)-563-1055, Fax:(713)-792-3535, [email protected]://openworks.mdanderson.org/ict/1000/thumbnail.jp
Personalized cancer therapy—leveraging a knowledge base for clinical decision-making
No full textNext-generation sequencing (NGS), also known as massively parallel sequencing, is rapidly being incorporated into oncology practice. Interpretation of genomic reports and selecting treatments based on the tumor's genomic analysis becomes more and more complicated for the treating oncologist because of the use of larger panels covering dozens to hundreds of genes and the amount of rapidly emerging clinical/translational data. To help guide personalized treatments in oncology, The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT) at MD Anderson Cancer Center has developed a knowledge base, available at https://personalizedcancertherapy.org or https://pct.mdanderson.org (PCT). This knowledge base provides information on the function of common genomic alterations and their therapeutic implications. Here, we describe how such genomic information can be used by health-care providers to identify genomically matched therapies.</jats:p
Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study
No full textFutibatinib; Advanced solid tumors; AberrationsFutibatinib; Tumores sólidos avanzados; AberracionesFutibatinib; Tumors sòlids avançats; AberracionsFutibatinib, a highly selective, irreversible FGFR1–4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1–3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement–positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy.
Significance:
This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1–4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population
A phase I trial of LHC165 single agent and in combination with spartalizumab in patients with advanced solid malignancies
No full textTumors sòlids avançatsAdvanced solid tumorsTumores sólidos avanzadosBackground
LHC165 is a Toll-like receptor (TLR)-7 agonist that generates an effective tumor antigen-specific T-cell adaptive immune response as well as durable antitumor responses. We aimed to evaluate the safety, tolerability, efficacy, dose-limiting toxicities, and pharmacokinetics (PK) of LHC165 single agent (SA) ± spartalizumab [PDR001; anti-programmed cell death protein 1 (PD-1)] in adult patients with advanced solid tumors.
Materials and methods
In this phase I/Ib, open-label, dose-escalation/expansion study, patients received LHC165 SA 100-600 μg biweekly through intratumoral (IT) injection and LHC165 600 μg biweekly + spartalizumab 400 mg Q4W through intravenous (IV) infusion.
Results
Forty-five patients were enrolled: 21 patients received LHC165 SA, and 24 patients received LHC165 + spartalizumab. The median duration of exposure was 8 weeks (range 2-129 weeks). No maximum tolerated dose was reached. Recommended dose expansion was established as LHC165 600 μg biweekly as SA and in combination with spartalizumab 400 mg Q4W. The most common drug-related adverse events (AEs) were pyrexia (22.2%), pruritus (13.3%), chills (11.1%), and asthenia (4.4%). The only serious AE (SAE) suspected to be related to the study drug was grade 3 pancreatitis (n = 1). Across all tumor types, overall response rate and disease control were 6.7% and 17.8%, respectively. Overall median progression-free survival (PFS) and immune-related PFS was 1.7 months. LHC165 serum PK demonstrated an initial rapid release followed by a slower release due to continued release of LHC165 from the injection site.
Conclusions
LHC165 demonstrated acceptable safety and tolerability both as SA and in combination with spartalizumab, and evidence of limited antitumor activity was seen in adult patients with relapsed/refractory or metastatic solid tumors.This work was supported by Novartis Pharmaceuticals Corporation. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation
Abstract 3291: Development of a novel prognostic scoring system for patient selection in immune checkpoint inhibitor phase 1 clinical trials
No full textAbstract
Purpose: To develop a prognostic scoring system for selecting patients for immune checkpoint inhibitor (ICI) phase 1 clinical trials.
Background: The Royal Marsden Hospital (RMH) and MD Anderson (MDA) prognostic scoring systems have been validated for patients in phase 1 clinical trials treated with cytotoxic chemotherapy and targeted therapy, but no such scoring system has been validated to help select patients entering ICI clinical trials.
Methods: We analyzed clinical data from patients treated in phase 1 ICI clinical trials (with anti-CTLA4 and anti-PD1 antibody therapy) at the MD Anderson Center for Targeted Therapy. Sixteen clinical factors were studied. Recursive partitioning analysis identified cut-points for each clinical factor and a Cox proportional hazards regression model was used to identify factors independently affecting overall survival.
Results: Among 172 patients treated with ICI therapy (105 CTLA4-based and 67 PD1-based) between January 2013 and November 2015, the median age was 60 years (range: 19-86 years) and 87 (51%) were male. The most common tumor types treated included renal cell carcinoma (n = 25; 15%), non-small cell lung cancer (n = 21; 12%), melanoma (n = 17; 10%), sarcoma (n = 14; 8%), gastrointestinal stromal tumors (n = 10; 6%), prostate cancer (n = 6; 3%), and colorectal cancer (n = 6; 3%). Seven factors were independently associated with significantly worse overall survival: age &gt;52 years (hazard ratio [HR] 1.59, 95% confidence interval [CI] 1.1-2.4), Eastern Cooperative Oncology Group performance status &gt;1 (HR 2.81, 95% CI 1.3-6.3), lactate dehydrogenase &gt;466 U/L (HR 2.1, 95% CI 1.4-3.2), platelet count &gt;300 × 109/L (HR 1.8, 95% CI 1.2-2.8), absolute neutrophil count &gt;4.9 × 109/L (HR 2.3, 95% CI 1.5-3.5), absolute lymphocyte count &lt;1.8 × 109/L (HR 3.3, 95% CI 1.9-5.7), and liver metastases (HR 1.8, 95% CI 1.2-2.6). An index was created whereby the cohort was divided into four risk groups based on the number of factors present: 0-2, 3, 4, or 5-6. Median overall survival was 24.2 months (0-2), 11.6 months (3), 8.0 months (4), and 3.8 months (5-6); log rank test, p &lt; 0.0001. The Harrell c-index of this scoring system was 0.72, indicating significant predictability.
Conclusion: We have developed a novel “MDA ICI” prognostic scoring system incorporating seven clinical parameters with prognostic significance for patients in phase 1 clinical trials treated with immune checkpoint inhibitors. Unlike in the RMH and MDA prognostic scoring systems, albumin level and number of metastatic sites did not independently correlate with overall survival. Prospective evaluation and external validation of our novel prognostic scoring system is warranted and may help better select patients for future clinical trials of checkpoint inhibitors.
Citation Format: Shiraj Sen, Kenneth Hess, David Hong, Aung Naing, Sarina Piha-Paul, Filip Janku, Siqing Fu, Holly Liu, Yunfang Jiang, Rahil Khanji, Daniel Karp, Apostolia Tsimberidou, Nizar Tannir, Funda Meric-Bernstam, Vivek Subbiah. Development of a novel prognostic scoring system for patient selection in immune checkpoint inhibitor phase 1 clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3291. doi:10.1158/1538-7445.AM2017-3291</jats:p
Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer
No full textCholangiocarcinoma; Futibatinib; Phase 2Colangiocarcinoma; Futibatinib; Fase 2Colangiocarcinoma; Futibatinib; Fase 2What is this summary about?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life.
What were the results?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib.
What do the results mean?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2)
Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial
No full textEfficacy and safety; Trastuzumab deruxtecan; Solid tumorsEficàcia i seguretat; Trastuzumab deruxtecan; Tumors sòlidsEficacia y seguridad; Trastuzumab deruxtecan; Tumores sólidosPurpose
Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)–directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non–small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.
Methods
This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS).
Results
At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.
Conclusion
Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.Supported by and sponsored by AstraZeneca in collaboration with Daiichi Sankyo. In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201). In collaboration with the authors, both AstraZeneca and Daiichi Sankyo assisted with data interpretation, writing of the report, reviewing the manuscript, and the decision to submit for publication
Supplemental Table S1: Terminology definitions as used by the Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center from Precision Oncology Decision Support: Current Approaches and Strategies for the Future
No full textTerminology definitions as used by the Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center</p
Challenges and perspective of drug repurposing strategies in early phase clinical trials
No full textDespite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies
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