Challenges and potential strategies utilizing external data for efficacy evaluation in small-sized clinical trials

PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

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Leveraging external data in the design and analysis of clinical trials in neuro-oncology

The Lancet Oncology ◽

10.1016/s1470-2045(21)00488-5 ◽

2021 ◽

Vol 22 (10) ◽

pp. e456-e465

Author(s):

Rifaquat Rahman ◽

Steffen Ventz ◽

Jon McDunn ◽

Bill Louv ◽

Irmarie Reyes-Rivera ◽

...

Keyword(s):

Clinical Trials ◽

External Data

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A methodology for the extraction and analysis of real-world radiographic and electronic medical record data to reconstruct treatment arms of historical prostate cancer clinical trials.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5033 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5033-5033

Author(s):

William David Lindsay ◽

Christopher A. Ahern ◽

Aaron Kamauu ◽

Robert Wilder ◽

Karen Chagin ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

Clinical Trials ◽

Real World ◽

Castration Resistant Prostate Cancer ◽

Efficacy Evaluation ◽

Real World Data ◽

Trial Treatment ◽

Picture Archiving And Communication

5033 Background: Real-world evidence (RWE), including synthetic comparator arms created from historical real-world data (RWD), has the potential to support the safety and efficacy evaluation of new medical products. However, many available RWD sources lack the details necessary to reliably identify patients comparable to clinical trial cohorts or to assess essential oncologic efficacy endpoints. This project demonstrates the ability to extract and analyze RWD to identify patients matching eligibility criteria to four historical clinical trials in metastatic castration-resistant prostate cancer (mCRPC), and calculate outcome measures. Methods: A total of 5,741 patients treated for prostate cancer at multiple institutions (2010-2020) were analyzed in two cohorts using data extracted from the EMR, Tumor Registry, Oncology Information System, and Picture Archiving and Communication System. Of 3,486 patients with prostate cancer in Cohort 1, 422 mCRPC patients were identified: those treated with ADT who achieved castration-level testosterone ( < 50 ng/dL), had evidence of metastatic disease, and exhibited rising PSA (PCWG2). These patients were further matched to four historical clinical trial treatment arms (COU-AA-301: 49, COU-AA-302: 143, AFFIRM: 30, PREVAIL: 79), based on prior chemotherapy and receipt of Abiraterone or Enzalutamide. Overall survival (OS) and time to skeletal related events (SRE) (pathological fracture, spinal compression, surgery to bone, and radiotherapy to bone) were calculated based on diagnosis and procedure codes using the Kaplan-Meier (KM) Estimator. Of 2,255 patients with prostate cancer in Cohort 2, 101 patients received Abiraterone or Enzalutamide and 59 patients had sufficient baseline and follow-up imaging to be scored. Radiographic progression-free survival (rPFS) was calculated from the start of treatment to the time of progression (RECIST 1.1) or loss to follow-up using the KM estimator. Results: In Cohort 1, median OS was 37.7 months (95% CI: 31.5-NR), and median time to SRE was 17.9 months (13.5-22.6). Median OS per patient cohort matched to historical trial treatment arm was COU-AA-301: 23.7 months (10.7-NR), COU-AA-302: 45.9 months (34.9-NR), AFFIRM: 35.3 months (6.34-NR), PREVAIL: 41.5 months (21.9-NR). In Cohort 2, median rPFS was 37.2 months (13.3-NR). Conclusions: The methodology employed in this analysis not only successfully identified a cohort of RWD patients similar to clinical trial-defined patients, but also curated sufficiently reliable data to calculate essential endpoints (e.g., rPFS). At scale, this methodology can be used to generate RWE, including synthetic comparator arms to support clinical trials with radiographic endpoints.

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Efficacy evaluation of anticancer agents in single-arm clinical trials: analysis of review reports from Pharmaceuticals and Medical Devices Agency

Acta Oncologica ◽

10.1080/0284186x.2021.1871946 ◽

2021 ◽

Vol 60 (2) ◽

pp. 143-148 ◽

Cited By ~ 1

Author(s):

Ken Hatogai ◽

Yuka Kato ◽

Chikara Hirase

Keyword(s):

Clinical Trials ◽

Medical Devices ◽

Anticancer Agents ◽

Efficacy Evaluation ◽

Review Reports

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Accelerated Development of COVID-19 Vaccines: Technology Platforms, Benefits, and Associated Risks

Vaccines ◽

10.3390/vaccines9070747 ◽

2021 ◽

Vol 9 (7) ◽

pp. 747

Author(s):

Ralf Wagner ◽

Eberhard Hildt ◽

Elena Grabski ◽

Yuansheng Sun ◽

Heidi Meyer ◽

...

Keyword(s):

Clinical Trials ◽

Vaccine Development ◽

Phase 1 ◽

Respiratory Illness ◽

Dose Finding ◽

Efficacy Evaluation ◽

Safety And Efficacy ◽

Vaccine Candidates ◽

Advantages And Disadvantages ◽

Technology Platforms

Multiple preventive COVID-19 vaccines have been developed during the ongoing SARS coronavirus (CoV) 2 pandemic, utilizing a variety of technology platforms, which have different properties, advantages, and disadvantages. The acceleration in vaccine development required to combat the current pandemic is not at the expense of the necessary regulatory requirements, including robust and comprehensive data collection along with clinical product safety and efficacy evaluation. Due to the previous development of vaccine candidates against the related highly pathogenic coronaviruses SARS-CoV and MERS-CoV, the antigen that elicits immune protection is known: the surface spike protein of SARS-CoV-2 or specific domains encoded in that protein, e.g., the receptor binding domain. From a scientific point of view and in accordance with legal frameworks and regulatory practices, for the approval of a clinic trial, the Paul-Ehrlich-Institut requires preclinical testing of vaccine candidates, including general pharmacology and toxicology as well as immunogenicity. For COVID-19 vaccine candidates, based on existing platform technologies with a sufficiently broad data base, pharmacological–toxicological testing in the case of repeated administration, quantifying systemic distribution, and proof of vaccination protection in animal models can be carried out in parallel to phase 1 or 1/2 clinical trials. To reduce the theoretical risk of an increased respiratory illness through infection-enhancing antibodies or as a result of Th2 polarization and altered cytokine profiles of the immune response following vaccination, which are of specific concern for COVID-19 vaccines, appropriate investigative testing is imperative. In general, phase 1 (vaccine safety) and 2 (dose finding, vaccination schedule) clinical trials can be combined, and combined phase 2/3 trials are recommended to determine safety and efficacy. By applying these fundamental requirements not only for the approval and analysis of clinical trials but also for the regulatory evaluation during the assessment of marketing authorization applications, several efficacious and safe COVID-19 vaccines have been licensed in the EU by unprecedentedly fast and flexible procedures. Procedural and regulatory–scientific aspects of the COVID-19 licensing processes are described in this review.

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Adjusting for Patient Crossover in Clinical Trials Using External Data: A Case Study of Lenalidomide for Advanced Multiple Myeloma

Value in Health ◽

10.1016/j.jval.2011.02.1182 ◽

2011 ◽

Vol 14 (5) ◽

pp. 672-678 ◽

Cited By ~ 8

Author(s):

K. Jack Ishak ◽

J. Jaime Caro ◽

Mark T. Drayson ◽

Meletios Dimopoulos ◽

Donna Weber ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

External Data

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Progress and Prospects on Vaccine Development against SARS-CoV-2

Vaccines ◽

10.3390/vaccines8020153 ◽

2020 ◽

Vol 8 (2) ◽

pp. 153 ◽

Cited By ~ 81

Author(s):

Jinyong Zhang ◽

Hao Zeng ◽

Jiang Gu ◽

Haibo Li ◽

Lixin Zheng ◽

...

Keyword(s):

Clinical Trials ◽

Severe Acute Respiratory Syndrome ◽

Infectious Diseases ◽

Vaccine Development ◽

Effective Means ◽

Efficacy Evaluation ◽

Novel Coronavirus ◽

And Control

In December 2019, the outbreak of pneumonia caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to a serious pandemic in China and other countries worldwide. So far, more than 460,000 confirmed cases were diagnosed in nearly 190 countries, causing globally over 20,000 deaths. Currently, the epidemic is still spreading and there is no effective means to prevent the infection. Vaccines are proved to be the most effective and economical means to prevent and control infectious diseases. Several countries, companies, and institutions announced their programs and progress on vaccine development against the virus. While most of the vaccines are under design and preparation, there are some that have entered efficacy evaluation in animals and initial clinical trials. This review mainly focused on the progress and our prospects on field of vaccine development against SARS-CoV-2.

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