scholarly journals A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1795
Author(s):  
Elisabete Cruz Da Silva ◽  
Marie-Cécile Mercier ◽  
Nelly Etienne-Selloum ◽  
Monique Dontenwill ◽  
Laurence Choulier
Keyword(s):  
Clinical Trials ◽  
Targeted Therapies ◽  
Standard Treatment ◽  
Cell Metabolism ◽  
Tyrosine Kinase Receptors ◽  
Newly Diagnosed ◽  
Glial Tumor ◽  
First Line ◽  
The Mean ◽  
And Migration

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.

Perceptions concerning clinical trials in oncology patients.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16533-e16533
Author(s):  
Dana Lee ◽  
Ju-Hsien Chao ◽  
Sandy Stevens ◽  
Goetz H. Kloecker
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Treatment Option ◽  
Phase 1 ◽  
Cancer Center ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
Oncology Patients

e16533 Background: Accrual to clinical trials among adult cancer patients is persistently low. Patient preference plays an important role in enrollment. To identify the reasons why patients decline study participation, it is important, to evaluate the perceptions of newly diagnosed oncology patients about clinical trials. Methods: Patients were given a ten-question survey reflective of their attitudes regarding clinical trials as a treatment option at their initial visit. The self-directed questionnaire was scored on an ordinate scale from strongly agree (1) to strongly disagree (5). Results: Ninety-two new patients were surveyed in the cancer - specific multispecialty clinics in an academic cancer center. The patients expected information relating to eligible clinical trials and privacy protection by university sponsored studies as they strongly concurred with “I expect my doctor to inform me about clinical trials that I am eligible for” (mean score 2.15, p=0.001) followed by “all possible measures to protect my privacy are likely to be taken in a clinical trial that is sponsored by a university” (2.36, p=0.36). The strongest disagreement was “If enrolled in a clinical trial, I am comfortable being assigned by a method such as ‘flipping a coin’ or ‘throwing a dice’” (3.73, p=0.001) and “I would be willing to participate in a clinical trial as a first line treatment option” (3.50, p=0.001). Industry sponsored trials, phase 1 trials, second line treatment trials, privacy concerns and investigator initiated trials and time commitment and altruistic reasons did not significantly deviate from the mean preference (2.5) by a one sample T-test analysis. Conclusions: Patients consider the option of clinical trials as important in their treatment, and expect to be informed by their oncologist about clinical trials. Newly diagnosed cancer patients perceive randomization and first line trials negatively. Since randomized data provides new standards for care and hope for improved treatment, patients and their families must be educated about their importance.

Overall survival (OS) by line of therapy (LOT) in Medicare-enrolled glioblastoma multiforme (GBM) patients (pts).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2039-2039
Author(s):  
Abdalla Aly ◽  
Prianka Singh ◽  
Beata Korytowsky ◽  
Homa Dastani ◽  
Lisa Ling ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Standard Treatment ◽  
Unmet Need ◽  
Additional Treatment ◽  
Second Line ◽  
First Line ◽  
Kaplan Meier ◽  
Comorbidity Index ◽  
Line Of Therapy

2039 Background: In clinical trials, the median OS of elderly GBM pts on standard treatment (tx) is ~9 months (mos) from diagnosis (dx), but has not been described in the real world (RW). This analysis describes RW OS for US Medicare GBM pts by LOT. Methods: GBM pts aged ≥66 years (y) were identified in SEER-Medicare (2007–2011). Pts were followed from dx to death, Medicare disenrollment or 12/31/2013. Systemic tx patterns were characterized as untreated (0L), ≥first line (1L+) and ≥second line (2L+). OS was estimated by the Kaplan-Meier method from dx for 0L, and from LOT start for 1L+ and 2L+. Results: Among 2533 eligible GBM pts (median age: 74 y; Charlson comorbidity index [CCI] ≥2: 13%), 49.9% received 1L+ and only 16.3% received 2L+. Median (1-year) OS for all pts was 5.3 mos (26%), range 1.6–10.7 mos (3–45%) depending on LOT, surgical resection (R) or Biopsy alone (B), tumor size, age, and CCI (Table). Conclusions: Receipt of tx has a significant impact on OS in Medicare GBM pts. This RW study shows that only 50% of pts receive tx, even though each LOT is associated with additional OS benefit. This suggests an unmet need for more efficacious therapies to allow additional treatment and improve outcomes. [Table: see text]

Age Significantly Influences Presentation and Patterns of Care in Patients with Newly Diagnosed Diffuse Large Cell Lymphoma (DLCL): Collective Data from 5 Centers Participating in the National Comprehensive Center Network (NCCN) NHL Outcomes Project.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1335-1335
Author(s):  
Maria Alma Rodriguez ◽  
Myron S. Czuczman ◽  
Jonathan W. Friedberg ◽  
Michelle E. Kho ◽  
Ann S. LaCasce ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Logistic Regression ◽  
Older Patients ◽  
International Prognostic Index ◽  
Newly Diagnosed ◽  
First Line ◽  
Independent Variables ◽  
Therapeutic Decisions ◽  
The Impact ◽  
To Receive

Abstract Background: Older patients with DLCL are underrepresented in clinical trials, and little is known about the impact of age on therapeutic decisions outside the clinical trial setting. Treatment for older individuals can be influenced by comorbidities, possibly limiting the use of proven aggressive therapies. We investigated the effects of age on patterns of presentation and treatment for patients with DLCL. Methods: Data from the 5 centers participating in the NCCN NHL Outcomes Project were used for analysis. Patients with newly diagnosed DLCL, receiving some or all of their care at the NCCN institutions, with first presention between 7/01/2000 to 6/30/2004 were included. Independent variables evaluated were stage, International Prognostic Index (IPI), Charlson comorbidity score, NCCN center, and age (≤ 60 and >60). Components of IPI were evaluated as separate independent variables. Fisher’s exact tests compared baseline characteristics between age groups. Univariate and multivariate logistic regression models were developed to identify factors associated with the receipt of anthracycline-based first-line therapy. Results: Of 417 patients presenting with newly diagnosed DLCL, 376 were eligible for analysis. Older patients (>60 years) accounted for 38% (142/376) of our cohort. The median age was 55.6 years; among older patients, over half were over 70. Older patients were significantly more likely to have HI/H IPI scores (52% vs. 27%, p=0.0001) and more than 2 major comorbidities (29% vs. 8%, p=0.0001). Overall, 18% (66/376) participated in first-line clinical trials, with no difference in participation by age (p=0.49). Among the 310 patients treated off protocol, 93% (289) received an anthracycline-containing first-line regimen. Older patients were less likely to receive anthracyclines [87% (105/120) vs. 97% (184/190)]. Among patients receiving anthracyclines, older patients were more likely to receive growth factor support [78% (82/105) vs.54% (100/184)]. In multivariable logistic regression adjusting for stage, comorbidity, and center, age was the only factor statistically significantly associated with treatment choice, with patients over 60 less likely to receive an anthracycline-based first-line regimen (OR=0.29; 95% CI=0.11 to 0.80 p=0.02). Conclusions: In a large cohort of patients with newly diagnosed DLCL, we found that older patients (>60 years) with DLCL had both higher risk disease, and more comorbidity at diagnosis. In our centers, there was no difference in clinical trail participation between older and younger patients; however, older patients were less likely to receive anthracyclines.

Deletion 17p in Unselected Newly Diagnosed Symptomatic Patients with Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5081-5081
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Maria Gkotzamanidou ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Elevated Serum ◽  
Initial Therapy ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
First Line ◽  
Poor Outcome ◽  
First Line Therapy ◽  
Line Therapy

Abstract Abstract 5081 Multiple myeloma is characterized by significant genetic heterogeneity. Cytogenetic abnormalities are almost always present and specific cytogenetic features may be associated with poor outcome. Deletion of the short arm of the chromosome 17, involving the p53 locus, has been associated with poor outcome of the disease and the frequency of this abnormality increases in more advanced phases of the disease. Novel drugs may overcome, to a certain degree, the poor prognosis that is associated with certain cytogenetic abnormalities, but recent data indicate that neither bortezomib nor thalidomide or lenalidomide may overcome the deleterious effect of del17p either in newly diagnosed or in patients with relapsed disease. These data come from selected patients who have been treated within the context of clinical trials, most of which included intensified treatment such as single or double transplants. In order to assess the prognostic importance of del 17p in unselected patients with multiple myeloma, most of which received upfront novel agents, we analyzed 168 consecutive previously untreated patients, who were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) who had available data on del17p, assessed by standard FISH methodology. Some of these patients were included in clinical trials, however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also included in the analysis, thus, being more representative of the general myeloma population. IMWG criteria were used for the assessment of response, progression-free (PFS) and overall survival (OS). Twenty-five (15%) of patients had del17p detected at initial diagnosis. The baseline clinical characteristics and conventional prognostic factors of patients with and without del17p were not significantly different. First line therapy was based on novel agents (thalidomide, bortezomib or lenalidomide) in 91% of patients and was similar for patients with or without del17p (p=0.887). Response to first line therapy was also similar (83% for those with del 17p versus 78% for those without, p=0.529). The quality of responses (CR, VGPR & PR) was also similar. Sixty percent of patients with a del17p and 39% of those without del17p have relapsed or progressed after initial therapy. The median progression free survival for patients with and without del17p was 18.5 versus 22.5 months respectively (p=0.065). In multivariate analysis, del17p was associated independently with shorter PFS (HR: 1.77, 95% CI: 1.021–3.07, p=0.042). Other factor that were independently associated with shorter PFS included age>65 years (p<0.001), ISS stage (p=0.028), low platelet counts (<130×109/L; p=0.032) and elevated serum LDH ≥300 IU/L (p<0.001). The median survival was significantly shorter for patients with del17p (29.5 versus 51 months, p=0.007). When we adjusted for other prognostic factors, including treatment with novel versus conventional agents, then the presence of del17 was independently associated with shorter survival (HR: 2.29, 95% CI: 1.15–4.6, p=0.019). Other factors associated with shorter survival included age >65 years (p=0.005), ISS-3 disease (p=0.038), low platelet counts (<130×109/L; p=0.005) and elevated serum LDH ≥300 IU/L (p=0.001). Importantly, median survival after first disease relapse for patients with del17p was 14 months while for patients without del17p was 42 months (p=0.01), despite the fact that in almost all patients novel agents were used as salvage treatment. In conclusion del17p remains an independent prognostic factor associated with poor survival in unselected patients with newly diagnosed MM, even when novel agents are used as initial therapy. Patients with del17p have very poor outcome after relapse, even with the use of novel agents as salvage therapy. Our data indicate that novel treatment and innovative strategies should be considered for these patients and that patients with del17p should be considered for participation in clinical trials of novel agents as soon as they relapse, since currently available treatment options offer limited benefit in these high risk patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Chemotherapy plus bevacizumab as an optimal first-line therapeutic treatment for patients with right-sided metastatic colon cancer: a meta-analysis of first-line clinical trials

ESMO Open ◽  
2020 ◽  
Vol 5 (2) ◽  
pp. e000605 ◽  
Author(s):  
Xia-Hong You ◽  
Yu-Huan Jiang ◽  
Zhou Fang ◽  
Fan Sun ◽  
Yao Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Targeted Therapies ◽  
Meta Analysis ◽  
Survival Ratio ◽  
Metastatic Colon Cancer ◽  
Wild Type ◽  
First Line ◽  
Metastatic Setting ◽  
The Right

BackgroundMonoclonal antibodies of anti-epidermal growth factor receptor (EGFR) have been recommended as first-line therapy for patients with left-sided metastatic colorectal cancer (mCRC) with wild-type RAS. The effect of tumour laterality on antivascular endothelial growth factor antibody and how to optimise targeted therapies for the right-sided cases remain controversial.Patients and methodsA comprehensive meta-analysis enrolling 16 first-line clinical trials was performed to evaluate the efficacy of chemotherapy alone and chemotherapy plus targeted therapies for patients with mCRC with right primary tumour site, and we validated the results in metastatic setting (14 trials containing 4306 patients with unresectable mCRC).ResultsHere, we found that progression-free survival (PFS) (combined HR 1.30, 95% CI 1.17 to 1.44) and overall survival (OS) (combined HR 1.46, 95% CI 1.32 to 1.62) of the right-sided patients were significantly inferior to the left-sided individuals receiving chemotherapy alone in overall population, regardless of race. Similar results were also observed in metastatic setting. OS of patients with left-sided mCRC receiving chemotherapy plus bevacizumab was superior to the right-sided individuals (combined median survival ratio (MSR)=1.23, 95% CI 1.08 to 1.39 for overall population; combined MSR=1.23, 95% CI 1.05 to 1.45 for metastatic setting), especially for wild-type RAS and mixed population. Moreover, the right-sided patients benefited more from chemotherapy plus bevacizumab comparing with chemotherapy alone in both overall population and metastatic setting. Importantly, the RAS-wild right-sided patients achieved longer PFS (combined HR 0.67, 95% CI 0.52 to 0.88) and OS (combined HR 0.74, 95% CI 0.56 to 0.98) from chemotherapy plus bevacizumab comparing with chemotherapy associated with anti-EGFR agents.ConclusionsPatients with right-sided mCRC show impaired chemosensitivity, and chemotherapy plus bevacizumab can be an optimal first-line therapeutic regimen for the RAS-wild patients with right-sided mCRC.

Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer

2021 ◽  
Vol 23 ◽  
Author(s):  
Dujuan Cao ◽  
Qianqian Song ◽  
Junqi Li ◽  
Yuanyuan Jiang ◽  
Zhimin Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Targeted Therapies ◽  
Poor Prognosis ◽  
Research Progress ◽  
Malignant Tumours ◽  
First Line ◽  
The Past ◽  
New Treatment

Abstract Pancreatic cancer is one of the most malignant tumours with a poor prognosis. In recent years, the incidence of pancreatic cancer is on the rise. Traditional chemotherapy and radiotherapy for pancreatic cancer have been improved, first-line and second-line palliative treatments have been developed, and adjuvant treatments have also been used in clinical. However, the 5-year survival rate is still less than 10% and new treatment methods such as targeted therapy and immunotherapy need to be investigated. In the past decades, many clinical trials of targeted therapies and immunotherapies for pancreatic cancer were launched and some of them showed an ideal prospect in a subgroup of pancreatic cancer patients. The experience of both success and failure of these clinical trials will be helpful to improve these therapies in the future. Therefore, the current research progress and challenges of selected targeted therapies and immunotherapies for pancreatic cancer are reviewed.

scholarly journals Transfusion Requirements and Hospitalization during First Line Treatment Among Newly Diagnosed Acute Myeloid Leukemia Patients Who Were Ineligible for Intensive Chemotherapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4849-4849
Author(s):  
Cat N. Bui ◽  
Thomas Marshall ◽  
Rajesh Kamalakar ◽  
Tracey Posadas ◽  
Jalaja Potluri
Keyword(s):  
Myeloid Leukemia ◽  
Transfusion Requirement ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
First Line ◽  
Employment Equity ◽  
Transfusion Independence ◽  
Transfusion Requirements ◽  
Equity Ownership ◽  
The Mean

Abstract Background: Newly diagnosed acute myeloid leukemia (ND AML) patients (pts) ineligible for intensive chemotherapy have limited treatment options. Most commonly used low intensity regimens are azacitidine (AZA), decitabine (DEC), or low-dose cytarabine (LDAC). These patients often have low blood counts that may contribute to poor quality of life (QoL) due to high risk for infections and may require transfusion of blood products. The objective of this study was to describe the patient characteristics, treatment patterns, and quantify the clinical outcomes (i.e., transfusion requirements infections and hospitalizations (hosp) among ND AML pts ineligible for intensive chemotherapy who received currently available therapies as first-line (1L) treatment in a real-world cohort. Methods: Eligible pts were found in the de-identified Optum© Clinformatics® Data Mart between 1/1/2010 and 6/30/2017 and had the following: AML at ≥2 encounters (ICD-9/10 codes) at least 30 days apart, ≥ 60 yrs. at diagnosis (dx), and ≥6 months (mo) benefit coverage before and ≥ 3 mo post dx. 1L treatment date (tx-index) was the date of first monotherapy (AZA, DEC, or LDAC) after AML diagnosis. 1L treatment duration was from tx-index to the end of study (EOS) defined as either end of 1L treatment, end of benefit coverage, relapse, or 12/31/2017. Transfusion independence (TI) during 1L treatment was defined as having neither platelets nor red blood cells (RBC) for ≥56 consecutive days (56-day TI). Patients with < 56 days of observation time from tx-index were not classified as achieving ≥56-day TI. During 1L treatment, transfusion support was defined as patients receiving either platelets and/or RBC regardless whether or not patients achieved ≥56-day TI. Sample selection and creation of analytic variables were performed using the Instant Health Data (IHD) platform (BHE, Boston, MA). Statistical analyses were undertaken with SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). Results: Among 785 eligible pts, 82.0% had Medicare Advantage, 59.2% were male, and the mean (median; range) age was 74.7 (75.0; range 60.0-89.0) yrs. The mean (median; range) baseline comorbidity score (measured by Quan Charlson Comorbidity Index, CCI) was 1.5 (1.0; 0-11), with an available follow-up period of 13.6 (10.6; 3.0-88.5) mo. As1L treatment, majority of pts received AZA (n=422, 53.8%) followed by DEC (n=337, 43.0%) and LDAC (n=26, 3.3%) and the mean (median; range) duration of treatment was 5.6 (3.7; 0.03-52.0) mo. A total of 4.5% (35) patients had major or minor GI hemorrhage, 1.9% (15) brain hemorrhage, and 48.7% (382) had infections of all grades (AZA: 202/422, 47.9%; DEC: 170/337, 50.5%; LDAC: 10/26, 38.5%). Prior to receiving 1L treatment, 48.0% (377/785) of patients required transfusion of either platelets and/or RBC (Table 1). During 1L treatment, 73.3% (575) of pts received transfusion support with a mean (median; range) of 8.5 (5.0; 1-181) transfusions of either platelets and/or RBC. Among 377 patients with transfusion support prior to 1L treatment, 33.7% (127/377) of patients achieved ≥ 56-day TI during 1L treatment (Table 1). Multivariate logistic regression showed pts with baseline transfusion requirement were less likely to achieve ≥56 consecutive day TI during 1L treatment vs. pts without baseline transfusion requirements (33.7% vs. 58.6%; OR = 0.37; 95% CI = 0.27 - 0.50; P < 0.001) with the current treatments. Among 785 patients during 1L treatment, the mean (median; range) number of hospitalizations was 0.91 (1.0; 0-8). A total of 53.1% (417) had ≥ 1 hospitalization; the mean (median; range) length of an inpatient stay was 10.9 (7.0; 1-97) days for these patients; and 49.4% (206), 75.1% (313), and 87.3% (364) of patients were admitted within 30, 60, 90 days of tx-index, respectively. Conclusions: This real-world study in ND AML patients showed transfusion burden on patients with the currently available non-intensive treatment with AZA and DEC being the most commonly used agents. Most (61.5%-80.1%) of the pts required transfusions for platelets and /or RBC and less than 40% (0%-38.6%) of the patients with baseline transfusion requirement achieved ≥56 consecutive days of transfusion independence anytime while receiving their 1L treatment. Additional research is warranted to understand the correlation between response to treatment and transfusion independence and subsequent impact on hospitalization and infections. Disclosures Bui: AbbVie: Employment. Marshall:AbbVie: Employment, Equity Ownership. Kamalakar:AbbVie: Employment. Posadas:AbbVie: Employment. Potluri:AbbVie: Employment, Equity Ownership.

scholarly journals The Real-World Characteristics and Outcomes of Newly Diagnosed Myeloma Patients Ineligible for Clinical Trials

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2350-2350 ◽  
Author(s):  
Mark A Fiala ◽  
James Dukeman ◽  
Keith Stockerl-Goldstein ◽  
Michael H. Tomasson ◽  
Tanya M Wildes ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Renal Function ◽  
Research Funding ◽  
Impaired Renal Function ◽  
Performance Status ◽  
Newly Diagnosed ◽  
First Line ◽  
The Past ◽  
Low Performance ◽  
First Line Treatment

Abstract Background: Over the past 2 decades, treatment advances have greatly improved the outcomes of patients with multiple myeloma (MM) and a glut of new knowledge about the biology, genetic profile, and prognostic factors of the disease have become available. However, much of this research has excluded patients with low performance status and those with impaired renal function or marrow reserve, therefore, relatively little is known about these patients who are largely ineligible for clinical trials. We performed a secondary data analysis of the Multiple Myeloma Research Foundation (MMRF) CoMMpass study to compare the disease manifestation, treatment, and prognosis of these patients with the overall MM population. Methods: Data was extracted from the open-access MMRF Researcher Gateway corresponding with interim analysis 8 from the CoMMpass study. The CoMMpass study is enrolling 1000 newly diagnosed MM patients who will be tracked longitudinally for 5 years. CoMMpass collects relevant clinical data as well as sequential tissue samples. Eligibility requirements for CoMMpass include: symptomatic MM with measureable disease by SPEP (≥1.0g/dL), UPEP (≥200mg/24 hours), or SFLC (≥10mg/dL); receiving an immunomodulator (IMID) and/or a proteasome inhibitor (PI) for initial MM treatment; and no prior malignancies in the past 5 years. We defined ineligibility for clinical trials as one or more of the following at time of MM diagnosis: ECOG performance status 3 or 4; creatinine ≥ 2.0mg/dL or receiving dialysis; absolute neutrophil count (ANC) <1.0x109/L or receiving growth factor support; or platelet count <50,000 x109/L or receiving platelet transfusion support. We compared the demographics, baseline presentation (International Staging System [ISS] stage, marrow and extramedullary disease burden, and chromosomal abnormalities), and first-line treatment of these patients with the overall population using bivariate analyses. We then performed a multivariate Cox regression analysis to compare event-free survival (EFS) defined as the interval from diagnosis to disease progression or death. The level of significance was set at 0.05 for all tests. Results: 799 patients were available for analysis. The median age was 64 years, 61% (486) were male, and 76% (611) were white. 23% (180) met the study definition of ineligibility for clinical trials. 5% (41/778) had low performance status, 16% (128/799) impaired renal function, 3% (22/799) impaired marrow reserve. Patients ineligible for clinical trials were similar to the rest of the population demographically, but were more likely have higher risk disease by ISS (70% stage 3 compared to 20%, p <0.0001), and deletion of 17p (11% compared to 6%, p <0.0298), and were less likely to receive IMIDs during first-line therapy (35% compared to 64%, p <0.0001). Interestingly, stem cell transplant (SCT) utilization was similar between the two groups (32% compared to 34%, p >0.05). Bivariate analyses are summarized in Table 1. After controlling for ISS stage, deletion of 17p, first-line treatment, and SCT utilization, patients ineligible for clinical trials had a 56% (aHR 1.56 [95% CI 1.09- 2.23], p = 0.0141) increase in risk of disease progression or death. Conclusion: Newly diagnosed MM patients with low performance status, impaired renal function, or marrow reserve have long been considered a high-risk group and, thus, most clinical trials have excluded them. IMIDs are contraindicated for these patients due to its myelotoxicity which further limits treatment options. After adjusting for differences in treatment, these patients still have poorer outcomes. Additional research is needed to better understand the needs of these patients and improve their outcomes. Table 1 Table 1. Disclosures Vij: Karyopharma: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Shire: Consultancy.

scholarly journals Current challenges in clinical development of “targeted therapies”: the case of acute myeloid leukemia

Blood ◽  
2015 ◽  
Vol 125 (16) ◽  
pp. 2461-2466 ◽  
Author(s):  
Elihu Estey ◽  
Ross L. Levine ◽  
Bob Löwenberg
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Leukemic Cells ◽  
Newly Diagnosed ◽  
Preclinical Models ◽  
First Choice ◽  
Acute Myeloid

Abstract A fundamental difficulty in testing “targeted therapies” in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including “organoids” and combinations of pharmacologic and genetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders.

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