Is It Time to Take MRD More Seriously? Relationship between MRD, Functional Cure and Life Expectancy Among Patients with Ph- B Cell Precursor ALL (BCP-ALL)

Background: Although BCP-ALL patients can achieve complete remission (CR) after induction chemotherapy, about 40% of them have residual leukemia cells in the bone marrow which is called minimal residual disease (MRD). Complete MRD response is defined as lack of MRD with an assay sensitivity of >= 10-4, which, if sustained for more than five years, may be regarded as a functional cure for ALL. On the contrary, presence of MRD is a signal of high risk of relapse leading to poor health outcomes. Blinatumomab is the only drug approved for BCP-ALL patients with MRD based on the results from BLAST, a single-arm phase 2 study conducted to assess the efficacy and safety of blinatumomab in adult BCP-ALL patients in CR with MRD. Currently, there is limited evidence on the relationship between MRD response and functional cure in ALL and life years gained. Objectives: The objective of this study was to assess the relationship between complete MRD response after blinatumomab treatment and 1) functional cure; 2) life years and quality adjusted life years (QALYs) gained among BCP-ALL patients with MRD. Methods: The relationship between MRD response, and clinical outcomes was analyzed using an existing cost-effectiveness analysis (CEA) based on combined decision tree and Markov cohort model over a lifetime horizon (50 years). The model includes survival conditional on treatment and MRD status for time to stem transplant, relapse and death. In the CEA, blinatumomab was compared to standard of care (SOC, defined as conventional maintenance chemotherapy). Clinical probabilities were derived primarily from blinatumomab clinical trial data and a non-interventional cohort study (used as a historical control). Life years gained were adjusted for quality based on utility values from trial EQ-5D scores. An annual discount rate of 3.5% was applied to estimate future outcomes. Results: In the base case, the complete MRD response rate was 83.6%, and blinatumomab yielded more life years gained (8.26 vs. 5.68) and more QALYs (6.56 vs. 4.44) compared with SOC. The proportion of patients achieving a functional cure was 43.59% in blinatumomab group vs. 26.78% in the SOC group. Clinical response varied with variations in MRD response rate at 75%, 78%, 80%, 85%. Specifically, when the complete MRD response rate increased from 75% to 85%, the total life years gained in the blinatumomab group increased by 0.51, QALYS increased by 0.42, and the proportion of patients cured increased by 3.05%. Conclusion: Achieving complete MRD response is associated with longer life expectancy, higher probability of being cured, and more QALYs among patients with BCP-ALL and MRD. Disclosures Shao: Amgen: Employment. Tiwana:Amgen: Employment, Equity Ownership. Despiegel:Amgen: Employment, Equity Ownership. Dirnberger:Amgen: Employment, Equity Ownership.

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Pomalidomide Plus Low-Dose Dexamethasone (POM + LoDEX) for Relapsed and Refractory Multiple Myeloma (RRMM): Results from a Pharmacoeconomic Evaluation

Blood ◽

10.1182/blood.v124.21.2649.2649 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2649-2649

Author(s):

Steve Schey ◽

Sujith Dhanasiri ◽

Dawn Lee ◽

Lars Sternas ◽

Xin Yu ◽

...

Keyword(s):

Cost Effectiveness ◽

Cost Effective ◽

Pharmacoeconomic Evaluation ◽

Base Case ◽

Employment Equity ◽

Lifetime Horizon ◽

Equity Ownership ◽

The Uk ◽

The Cost ◽

Over Time

Abstract Background: Multiple myeloma remains an incurable disease, placing a significant burden on patients (pts), families, and healthcare systems. Bortezomib (BORT) and IMiDs® immunomodulatory agents (thalidomide and lenalidomide [LEN]) have improved progression-free survival (PFS), time to progression, and overall survival (OS). However, over time, nearly all pts become refractory which greatly impacts prognosis (median OS, 3-9 mos). In the absence of approved treatments, guidelines recommend clinical trials or retreatment with agents that were previously effective, but published data in the appropriate pt population for current care (CC) options are limited to those from small, observational, early-phase studies. There is a need for newer effective treatments; however, access is increasingly being determined by the demonstration of both clinical and economic value. POM + LoDEX demonstrated a significant OS benefit vs. high-dose dexamethasone (HiDEX) in the pivotal phase 3 MM-003 study (San Miguel, Lancet Oncol, 2013). POM + LoDEX has EU approval in RRMM pts in whom BORT and LEN failed. Objective: Explore the cost-effectiveness of POM + LoDEX vs. CC from a UK and Ireland healthcare payer perspective. Methods: A de novo pharmacoeconomic evaluation was conducted to compare costs and outcomes of POM + LoDEX to CC in the UK and Ireland. CC included BORT retreatment (intravenous [IV] or subcutaneous), LEN (oral), and bendamustine (IV) regimens. Efficacy data were sourced from MM-003 and 2 observational studies: a dataset for CC (Gooding, 2013; n = 30 pts primarily treated with BORT, bendamustine, or LEN; 100% received prior BORT and LEN) and a dataset for BORT + LEN (Jimenez-Zepeda, 2013; n = 30, 80% received prior BORT, 73% prior LEN). Validation of the approach and all model assumptions was achieved through extensive clinical and health economic expert consultation and by comparing comparator arm outcomes from observational data to the MM-003 (HiDEX) control arm data. The health economic model used a partitioned survival structure with OS and PFS parametric curves fitted to the datasets to estimate the number of pts at each time point expected to be preprogression, postprogression, or dead. Time to treatment failure curves were estimated to allow treatment discontinuation modelling. EQ-5D data, collected as part of MM-003, were used to inform quality of life (QOL) weights. A utility regression equation was developed to account for important covariates and allow utility to vary over time. The economic evaluation included the cost of treatment, administration, monitoring, tests, adverse events (AEs), blood transfusions, concomitant medication, and terminal care. Costs are presented in US dollars using an exchange rate of 0.74 per € and 0.58 per £. Costs and outcomes were modeled to estimate cost per life year (LY) and cost per quality-adjusted life year (QALY) gained over a lifetime horizon. Results: In the base-case analysis, POM + LoDEX was associated with a total incremental cost of $59,250 per pt over a lifetime horizon compared with CC (Table 1). Pts who receive POM + LoDEX are predicted to live for a mean of 2.2 years, compared with 1.2 years with CC. This represents an additional 0.6 QALYs. The model predicts a deterministic incremental cost-effectiveness ratio (ICER) of $100,920/QALY compared with CC, while the probabilistic ICER obtained through 1000 probabilistic model runs was consistent at $101,947/QALY. Table 1 : Base-Case Cost-Effectiveness Results Model Results POM + LoDEX CC Difference Clinical outcomes Median OS, mos 12.7 5.5 7.2 Mean predicted life-years (over a pt lifetime) 2.2 1.2 1.0 QALYs 1.3 0.7 0.6 Cost outcomes, US dollars Medication and administration $84,698 $29,880 $54,818 Monitoring $8230 $4489 $3741 AE management (outpatient visits and hospitalization) $7135 $6444 $691 Total $100,063 $40,813 $59,250 ICER—Cost/LY $58,112 ICER—Cost/QALY $100,920 Conclusion: There are limited alternative treatment options available in the UK and Ireland for RRMM pts. None have a proven effect on survival leaving pts to face potentially ineffective retreatments. End-of-life drugs that significantly improve survival and QOL and address unmet need can be considered to be cost-effective at a higher “willingness to pay” threshold. POM, an oral therapy with significant PFS, survival, and QOL with a known safety profile, is likely to be a cost-effective use of healthcare resources. Disclosures Dhanasiri: Celgene Corp: Employment, Equity Ownership. Lee:Celgene Corp: Consultancy. Sternas:Celgene Corp: Employment, Equity Ownership. Yu:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Elvidge:Celgene Corp: Consultancy.

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Impact of Post-Hematopoietic Cell Transplant (HCT) Survival on Cost-Effectiveness of CPX-351 Versus 7+3 in the Treatment of Therapy-Related AML or AML-MRC in the United States

Blood ◽

10.1182/blood-2018-99-112252 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5837-5837

Author(s):

Anuraag Kansal ◽

Odette Reifsnider ◽

Lora Todorova ◽

Anna Coughlan ◽

Kathleen F. Villa

Keyword(s):

United States ◽

Cost Effectiveness ◽

Life Expectancy ◽

The United States ◽

Cell Transplant ◽

Employment Equity ◽

Treatment Pathways ◽

Life Years ◽

Equity Ownership ◽

The Impact

Abstract Background: A central goal of treatment for high-risk AML is enabling patients to receive HCT. CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. A large randomized, open-label, multicenter, phase 3 trial demonstrated superior outcomes, including significantly longer overall survival and a larger fraction of patients reaching HCT, for CPX-351 versus conventional cytarabine/daunorubicin (7+3 regimen) in patients aged 60 to 75 years with newly diagnosed therapy-related AML (tAML) or AML with myelodysplasia-related changes (AML-MRC; Lancet JE, et al. J Clin Oncol. 2018). In order to estimate the cost-effectiveness of treatments for AML, and for CPX-351 in particular, it is necessary to extrapolate survival of patients undergoing HCT to the long-term. The objective of this analysis was to assess the impact of different estimates of post-HCT mortality on cost-effectiveness of CPX-351. Methods: An existing economic model of CPX-351 versus 7+3 for the treatment of tAML or AML-MRC was used to project lifetime health and cost outcomes. The modeled population included 30% patients <60 years of age and 70% between 60 and 75 years of age. The model uses a survival-partition approach, with distinct survival curves for cohorts defined by treatment pathways (response and transplantation). Projected life expectancy for each cohort was estimated based on trial data (for those 60-75 years of age), US population life-tables, and published data. For patients younger than age 60, response rates were adjusted based on published literature. Standardized mortality ratio (SMR) values following HCT were selected individually for the younger and older cohorts. SMR values were calibrated in the model to match the literature finding that post-HCT mortality results in a loss of approximately 30% of life expectancy. This yielded an SMR of 2.25 for older patients and 4.0 for younger patients. Values ranged from 1.0 to 4.0 in sensitivity analyses based on recent appraisals by the United Kingdom's National Institute for Health and Care Excellence (NICE). Model outputs included survival, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Results: In the base case with different SMR values by age, the model yielded a predicted ICER value of $111,841/QALY in the overall cohort, which compares favorably to the typical $150,000/QALY threshold (Bae 2014) for good value care in the United States. Using the same estimates of SMR in all patients yielded ICER values of $125,280/QALY and $151,793/QALY for SMR values of 2.25 and 4.0, respectively. Assuming no excess mortality post-HCT relative to the general population, using an SMR of 1.0, resulted in modest improvements in cost-effectiveness (ICER = $102,298/QALY). Conclusions: CPX-351 is a cost-effective option for the treatment of patients with tAML or AML-MRC when accounting for potentially increased mortality following HCT. Disclosures Kansal: Jazz Pharmaceuticals: Consultancy. Reifsnider:Jazz Pharmaceuticals: Consultancy. Todorova:Jazz Pharmaceuticals: Employment, Equity Ownership. Coughlan:Jazz Pharmaceuticals: Consultancy. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership, Other: Stock and stock options.

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Impact of Somatic Gene Mutations on Response to Lenalidomide (LEN) in IPSS Lower-Risk Myelodysplastic Syndromes (MDS) Patients (Pts) without Del(5q) and Ineligible for or Refractory to Erythropoiesis-Stimulating Agents (ESAs)

Blood ◽

10.1182/blood.v128.22.225.225 ◽

2016 ◽

Vol 128 (22) ◽

pp. 225-225 ◽

Cited By ~ 2

Author(s):

Valeria Santini ◽

Pierre Fenaux ◽

Aristoteles Giagounidis ◽

Uwe Platzbecker ◽

Alan F List ◽

...

Keyword(s):

Lower Risk ◽

Research Funding ◽

Response Rate ◽

Single Gene ◽

Gene Mutations ◽

Advisory Board ◽

Employment Equity ◽

Mutation Status ◽

Somatic Gene ◽

Equity Ownership

Abstract Background: Somatic gene mutations occur in the majority of MDS pts; specific mutations and high mutation frequency have prognostic relevance (Papaemmanuil et al. Blood. 2013;122:3616-27). Evaluation of somatic mutations may support the diagnosis of MDS and guide treatment (Tx) selection. The phase 3 randomized MDS-005 study compared LEN and placebo (PBO) Tx in red blood cell transfusion-dependent (RBC-TD) non-del(5q) lower-risk MDS pts ineligible for or refractory to ESAs. Deletions in chromosome 5q are associated with a high response rate to LEN in MDS pts; however, no mutations have been definitively associated with a predictable clinical response to LEN in non-del(5q) MDS. Aim:To investigate the relationship between somatic gene mutations detected by targeted next-generation sequencing (NGS) and response and overall survival (OS) in lower-risk non-del(5q) MDS pts treated with LEN in the MDS-005 study. Methods: Eligible pts were: RBC-TD (≥ 2 units packed RBCs/28 days 112 days immediately prior to randomization) with International Prognostic Scoring System defined Low-/Intermediate-1-risk non-del(5q) MDS; ineligible for ESA Tx (serum erythropoietin > 500 mU/mL); or unresponsive or refractory to ESAs (RBC-TD despite ESA Tx with adequate dose and duration). 239 pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40-60 mL/min) or PBO. DNA was isolated from bone marrow mononuclear cells or whole blood collected at screening from a subset of pts who gave informed consent for this exploratory biomarker analysis and had adequate tissue for analysis. Targeted NGS of 56 genes was performed at Munich Leukemia Laboratory; average sequencing coverage was 2,000-5,000-foldand the variant allele frequency detection cutoff was 3%. Target regions varied by gene, including all exons to hotspots. For association tests, mutant variants (heterozygous or homozygous) were scored as 1 (mutant) or 0 (wildtype) for gene-level analyses. A Fisher exact test was used to test association of mutation status with response. Median OS was calculated by the Kaplan-Meier method. Hazard ratios and 95% confidence intervals were determined by a non-stratified Cox proportional hazards model. A log-rank test was used to test treatment effect with OS for single gene mutation status. Results: The biomarker cohort included 198 of 239 pts (83%; LEN n = 130, PBO n = 68). At least 1 mutation was detected in 30/56 (54%) genes and 173/198 (87%) pts. The most frequently mutated genes were SF3B1 (59%), TET2 (33%), ASXL1 (23%), and DNMT3A (14%); the most frequent co-mutations were SF3B1/TET2 (23%), SF3B1/DNMT3A (10%), SF3B1/ASXL1 (10%), and TET2/ASXL1 (9%) (Figure). Of 116 pts with SF3B1 mutations, 115 (99%) had ≥ 5% ring sideroblasts. The 56-day RBC transfusion-independence (RBC-TI) response rate was significantly lower in LEN-treated ASXL1 mutant pts vs wildtype pts (10% vs 32%, respectively; P = 0.031). At 168 days, the RBC-TI response rate was still lower in LEN-treated ASXL1 mutant pts vs wildtype pts (7% vs 22%); however, the difference was not significant (P = 0.101). LEN-treated DNMT3A mutant pts had a higher 56-day RBC-TI response rate vs wildtype pts (44% vs 25%); however, this difference did not reach significance (P = 0.133) due to the small sample size. RBC-TI response rate with LEN was similar regardless of total number of mutations per pt. Higher numbers of mutations were significantly associated (P = 0.0005) with worse median OS. Mutation in any of the genes associated with a negative prognosis reported by Bejar et al. (N Engl J Med. 2011;346:2496-506) was also significantly associated (P = 0.0003) with worse median OS.However, OS was not significantly different in LEN- vs PBO-treated pts based on any single gene mutation status. Conclusions: In this group of lower-risk RBC-TD non-del(5q) MDS pts, somatic mutations in genes recurrently mutated in myeloid cancers were detected in 87% of pts. SF3B1 mutations (alone or in combination) were most frequent and not associated with response to LEN. ASXL1 mutant pts had a significantly lower LEN response rate vs wildtype pts, whereas DNMT3A mutant pts had a trend for improved LEN response. Median OS was influenced by mutations, but not significantly modified by LEN. Determining predictive clinical markers for Tx response in non-del(5q) MDS pts remains challenging; nevertheless, there is a significant need to identify pt subsets who may be responsive to LEN Tx. Figure. Figure. Disclosures Santini: Novartis: Consultancy, Honoraria; Amgen: Other: advisory board; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astex: Other: advisory board. Fenaux:Celgene, Janssen, Novartis, Astex, Teva: Research Funding; Celgene, Novartis, Teva: Honoraria. Giagounidis:Celgene Corporation: Consultancy. Platzbecker:Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding. Zhong:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Mavrommatis:Discitis DX: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership. Hoenekopp:Celgene Corporation: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties, Research Funding.

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Clinical and Economic Impact of ‘ROS1-Testing’ Strategy Compared to a ‘No- ROS1-Testing’ Strategy in Advanced NSCLC in Spain

10.21203/rs.3.rs-1103970/v1 ◽

2021 ◽

Author(s):

Federico Rojo ◽

Esther Conde ◽

Héctor Torres ◽

Luis Cabezón-Gutiérrez ◽

Dolores Bautista ◽

...

Keyword(s):

Markov Model ◽

Economic Impact ◽

Expert Opinion ◽

Advanced Nsclc ◽

Direct Costs ◽

Base Case ◽

Molecular Testing ◽

Testing Strategy ◽

Lifetime Horizon ◽

Life Years

Abstract Background: Detection of the ROS1 rearrangement is mandatory in patients with advanced or metastatic non-small cell lung cancer (NSCLC) to allow targeted therapy with specific inhibitors. However, in Spanish clinical practice ROS1 determination is not yet fully widespread. The aim of this study is to determine the clinical and economic impact of sequentially testing ROS1 in addition to EGFR and ALK in Spain.Methods: A joint model (decision-tree and Markov model) was developed to determine the cost-effectiveness of testing ROS1 strategy versus a no-ROS1 testing strategy in Spain. Distribution of ROS1 techniques, rates of testing, positivity, and invalidity of biomarkers included in the analysis (EGFR, ALK, ROS1 and PD-L1) were based on expert opinion and Lungpath real-world database. Treatment allocation depending on the molecular testing results was defined by expert opinion. For each treatment, a 3-states Markov model was developed, where progression free survival (PFS) and overall survival (OS) curves were parameterized using exponential extrapolations to model transition of patients among health states. Only medical direct costs were included (€ 2021). A lifetime horizon was considered and a discount rate of 3% was applied for both costs and effects. Both deterministic and probabilistic sensitivity analyses were performed to address uncertainty.Results: A target population of 8,755 patients with advanced NSCLC (non-squamous or never smokers squamous) entered the model. Over a lifetime horizon, the ROS1 testing scenario produced additional 157.5 life years and 121.3 quality-adjusted life years (QALYs) compared with no-ROS1 testing scenario. Total direct costs were increased up to € 2,244,737 for ROS1 testing scenario. The incremental cost-utility ratio (ICUR) was 18,514 €/QALY. Robustness of the base-case results were confirmed by the sensitivity analysis.Conclusions: Our study shows that ROS1 testing in addition to EGFR and ALK is a cost-effective strategy compared to no-ROS1 testing, and it generates more than 120 QALYs in Spain over a lifetime horizon. Despite the low prevalence of ROS1 rearrangements in NSCLC patients, the clinical and economic consequences of ROS1 testing should encourage centers to test all advanced or metastatic NSCLC (non-squamous and never-smoker squamous) patients.

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P1225Cost-effectiveness of evolocumab in patients with high atherosclerotic cardiovascular risk in Sweden

European Heart Journal ◽

10.1093/eurheartj/ehz748.0183 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

P Lindgren ◽

E Hagstrom ◽

B Van Hout ◽

G Villa ◽

M Urbich ◽

...

Keyword(s):

Clinical Trial ◽

Cost Effectiveness ◽

Screening Program ◽

Patient Characteristics ◽

Lipid Lowering ◽

List Price ◽

Base Case ◽

Atherosclerotic Cardiovascular Disease ◽

Lifetime Horizon ◽

Life Years

Abstract Background/Introduction Elevated low-density lipoprotein cholesterol (LDL-C) is one of the most important modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD). Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, is indicated for the reduction of CV risk by lowering LDL-C. Purpose Assess the cost-effectiveness of evolocumab added to standard of care (SoC), maximally tolerated lipid-lowering treatment, in two patient populations for which evolocumab is reimbursed in Sweden: (1) patients with ASCVD with LDL-C ≥2.5 mmol/L on SoC, and (2) heterozygous familial hypercholesterolemia (HeFH) patients without ASCVD with LDL-C ≥3.0 mmol/L on SoC. Methods A previously published Markov model was adapted to the Swedish context. The model incorporated real-world CV event (CVE) rates (myocardial infarction, ischemic stroke and CV death). In patients with ASCVD, a CVE rate of 6.3/100 patient-years was obtained from Swedish national registries. In HeFH patients without ASCVD, a CVE rate of 4.5/100 patient-years was obtained from a national screening program in the Netherlands. ASCVD patient characteristics were obtained from Swedish national registries. HeFH patient characteristics were obtained from the RUTHERFORD-2 clinical trial. The model used an evolocumab LDL-C reduction of 59%, as observed in the FOURIER CV outcomes clinical trial, and the relationship between LDL-C lowering and CVE reduction from the Cholesterol Treatment Trialists' Collaboration (CTTC) 2010 meta-analysis (base case) or FOURIER (scenario). An annual evolocumab list price (before discount) of SEK 48,759 [€ 4,632] (1 SEK = € 0.095) was considered. Costs and health outcomes were evaluated over a lifetime horizon from a societal perspective. Results In the base case, for patients with ASCVD with LDL-C ≥2.5 mmol/L on SoC, the addition of evolocumab was associated with: a 0.30 reduction in the lifetime per-patient CVE rate, increased costs of SEK 413,835 and increased quality-adjusted life years (QALY) of 0.67, yielding an incremental cost-effectiveness ratio (ICER) of SEK 615,393 [€ 58,462] per QALY gained. In the base case, for HeFH patients without ASCVD with LDL-C ≥3.0 mmol/L on SoC, the addition of evolocumab was associated with: a 0.57 reduction in the lifetime per-patient CVE rate, increased costs of SEK 701,200 and increased QALY of 1.39, yielding an ICER of SEK 503,710 [€ 47,852] per QALY gained. In the scenario analysis, ICER were SEK 539,846 [€ 51,285] and SEK 462,961 [€ 43,981] per QALY, respectively. Conclusions These results indicate the addition of evolocumab to SoC may be considered cost-effective in Sweden. Indeed, based on these data, the Swedish Dental and Pharmaceutical Benefits Agency (TLV) recently granted expanded reimbursement for evolocumab (submission 2138/2018), which led to a positive national recommendation in the patient populations described above. Acknowledgement/Funding This study was sponsored by Amgen.

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Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-131481 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5768-5768

Author(s):

Adekemi Taylor ◽

Martine Allard ◽

Cecile Kresja ◽

Dana Lee ◽

Greg Slatter

Keyword(s):

Multiple Myeloma ◽

Steady State ◽

Solid Tumors ◽

Upper Bound ◽

Myeloid Leukemia ◽

Employment Equity ◽

Equity Ownership ◽

The Mean ◽

The Relationship ◽

Mdm2 Inhibitor

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

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A Phase I/II Study of CYT387, An Oral JAK-1/2 Inhibitor, In Myelofibrosis: Significant Response Rates In Anemia, Splenomegaly, and Constitutional Symptoms

Blood ◽

10.1182/blood.v116.21.460.460 ◽

2010 ◽

Vol 116 (21) ◽

pp. 460-460 ◽

Cited By ~ 14

Author(s):

Animesh Pardanani ◽

Geeta George ◽

Terra Lasho ◽

William J. Hogan ◽

Mark R. Litzow ◽

...

Keyword(s):

Phase I ◽

Response Rate ◽

Red Cell ◽

Spleen Size ◽

Jak Inhibitors ◽

Employment Equity ◽

Previously Treated ◽

Equity Ownership ◽

Red Cell Transfusion ◽

Grade 3

Abstract Abstract 460 Background: CYT387 is a potent JAK-1/2 inhibitor that suppresses the in vitro growth of cells harboring JAK2V617F (Leukemia 2009;23:1441) and was effective in a murine model of myeloproliferative neoplasms (MPN) (Blood 2010;115:5232). Aims/Methods: To assess the safety, tolerability, and pharmacokinetic behavior of CYT387 in a Phase I dose-escalation study in patients with high- or intermediate-risk primary myelofibrosis (PMF) and post-PV or post-essential thrombocythemia (ET) myelofibrosis. The secondary objective was evaluation of preliminary efficacy. CYT387 was administered orally once daily in 28-day cycles. Once dose-limiting toxicity (DLT) was identified, a dose-confirmation cohort initiated treatment at the maximum tolerated dose (MTD) or lower. Result: Thirty six subjects (median age 64 years) have been enrolled (targeted accrual 120); 18 each in the dose escalation and dose confirmation phases. Twenty-three subjects had PMF, 8 post-PV MF, and 5 post-ET MF; 81% were JAK2V617F-positive. Median palpable spleen size was 18 cm and 20 subjects (56%) were red cell transfusion-dependent at study entry. Prior treatment included JAK inhibitors (9 and 1 subjects with INCB018424 and TG101348, respectively) and pomalidomide in 9 patients. The median treatment duration to date is 15 weeks (range 4–38). Dose-linear plasma exposures were observed up to 300 mg/day, with mean elimination T1/2 at steady state ranging from 3.9 to 5 hours across doses. Toxicity: All 36 subjects were evaluable for toxicity. At 400 mg/day, 2 of 6 subjects experienced DLT (1 each with asymptomatic grade 3 hyperlipasemia and grade 3 headache that were reversible upon holding drug); consequently, the MTD was declared at 300 mg/day. In the dose-confirmation phase, subjects were started at one of 2 dose levels that were deemed clinically effective: 150 mg/day (n=15) and 300 mg/day (n=3). Thirty-five subjects are currently on active therapy: 100 mg/day (n=2), 150 mg/day (n=20), 300 mg/day (n=10), and 400 mg/day (n=3). CYT387 was well tolerated. No grade 4 non-hematological toxicities were observed. Grade 3 non-hematologic adverse events were infrequent and included increased transaminases (n=2), increased alkaline phosphatase (n=2), headache/head pressure (n=2), increased lipase (n=1), and QTc prolongation (n=1). Thirteen (36%) subjects experienced “first-dose effect” characterized by grade 1 lightheadedness and hypotension; this phenomenon was self-limited and generally resolved within 3–4 hours with rare recurrence. Grade 3/4 thrombocytopenia was seen in 8 (22%) subjects, and treatment-emergent grade 3 anemia was seen in 1 subject only (3%). Treatment-emergent grade 3/4 neutropenia was not observed. Efficacy: Thirty two of 36 subjects who completed at least 1 cycle were eligible for response assessment: Anemia: Twenty two subjects were evaluable for anemia response (baseline Hgb <10 g/dL or red cell transfusion-dependent). Of these, 9 subjects (41%) achieved the threshold of response for “Clinical Improvement (CI)” per the International Working Group for MPN Research and Treatment (IWG-MRT) criteria, including 2 of 4 subjects who were previously treated with INCB018424. An additional 5 subjects experienced a >50% reduction in transfusion requirement, thus increasing the total anemia response rate to 63%. Splenomegaly: Thirty of 32 evaluable subjects had splenomegaly at baseline: median 20 cm; range 10–32 cm. Twenty nine subjects (97%) had some degree of spleen size reduction (median 9 cm; range 2–18 cm): 11 (37%) patients have achieved a minimum 50% decrease in palpable spleen size, thus qualifying them for a CI, including 3 of 8 subjects (38%) who were previously treated with INCB018424. Constitutional symptoms: The proportion of patients with the following symptoms at baseline, are: fatigue (97%), pruritus (22%), night sweats (38%), cough (13%), bone pain (28%), and fever (16%). At last follow up, improvement (complete resolution) in these symptoms was reported by 68% (16%), 86% (57%), 83% (75%), 75% (50%), 78% (44%), and 100% (100%), respectively. Conclusion: CYT387 is first-in-class of the JAK inhibitors with a significant response rate in anemia in myelofibrosis patients. The drug also shows substantial activity in reducing spleen size and controlling constitutional symptoms. CYT387 is well tolerated, and treatment responses have been seen both at (300 mg/day) and below (150 mg/day) the MTD. Disclosures: Pardanani: Cytopia Inc.: Research Funding. Off Label Use: Clinical trial data for CYT387 use in Myelofibrosis. Fida:YM Biosciences Australia: Employment, Equity Ownership. Burns:YM Biosciences Australia: Employment, Equity Ownership. Smith: YM Biosciences Australia: Employment, Equity Ownership.

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Ruxolitinib Provides Reductions in Splenomegaly Across Subgroups: An Analysis of Spleen Response in the COMFORT-II Study

Blood ◽

10.1182/blood.v118.21.279.279 ◽

2011 ◽

Vol 118 (21) ◽

pp. 279-279 ◽

Cited By ~ 6

Author(s):

Claire N. Harrison ◽

Jean-Jacques Kiladjian ◽

Heinz Gisslinger ◽

Dietger Niederwieser ◽

Francesco Passamonti ◽

...

Keyword(s):

Board Of Directors ◽

Response Rate ◽

Response Rates ◽

Risk Category ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Starting Dose ◽

Secondary Endpoints ◽

Equity Ownership

Abstract Abstract 279 Background: COMFORT-II is a randomized, open-label, phase 3 study evaluating the safety and efficacy of ruxolitinib, a potent and selective oral inhibitor of JAK1 and JAK2, in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), or post-essential thrombocythemia-MF (PET-MF). Patients who received ruxolitinib had significantly greater reductions in spleen volume compared with those who received best available therapy (BAT). The primary and key secondary endpoints of the study were both met: the proportion of patients achieving ≥35% reduction in spleen volume at week 48 (28.5%, ruxolitinib; 0%, BAT; P <.0001) and week 24 (31.9%, ruxolitinib; 0%, BAT; P <.0001), respectively. Subgroup analysis was performed on both the 48- and 24-week endpoints. Methods: In the COMFORT-II study, 219 patients were randomized (2:1) to receive ruxolitinib (15 or 20 mg twice daily [bid] based on the baseline platelet count [100– 200 × 109/L or >200 × 109/L, respectively]) or BAT of the investigator's choice. The proportions of ruxolitinib-treated patients achieving the primary and key secondary endpoints were analyzed by subgroup for gender (male or female), age (≤65 or >65 years), starting dose (15 or 20 mg bid), baseline MF type (PMF, PPV-MF, or PET-MF), previous hydroxyurea (hydroxycarbamide) use (yes or no), baseline palpable spleen length (≤10 or >10 cm), baseline spleen volume (>median or ≤median), JAK2V617F mutation (presence or absence), and International Prognostic Scoring System (IPSS) risk category (intermediate-2 or high) (Cervantes F, et al, Blood, 2009;113(13):2895–2901). In addition, the relationships between these factors and spleen volume reduction were investigated by multivariate logistic regression. Results: The proportion of patients in each subgroup with ≥ 35% reduction in spleen volume from baseline at week 48 is shown below (Figure). BL, baseline; HU, hydroxyurea. The response rate was higher in patients receiving ruxolitinib than in patients receiving BAT in all subgroups; no patients in the BAT group reached a ≥35% reduction in spleen volume at week 48. All subgroups receiving ruxolitinib responded and all subgroup comparisons had overlapping 95% confidence intervals. At week 24, a trend for a higher response rate was observed in patients who received a starting dose of 20 mg bid compared with those who received a starting dose of 15 mg bid; however, the response rates among these patients at week 48 were not different. No significant difference in response rates was observed between patients with the JAK2V617F mutation compared with those without the mutation. Results of the subgroup analysis were confirmed by the multivariate models. A significant effect of the ruxolitinib starting dose was seen when response rates were modeled at week 24 but not when modeled at week 48. Conclusions: Recent findings from the COMFORT-II study show that patients who received ruxolitinib had significantly greater reductions in splenomegaly than did patients who received BAT. In this analysis, ruxolitinib was shown to be more effective than BAT at reducing spleen volume in all patient subgroups regardless of gender, age, mutation status, IPSS risk category, baseline spleen size, MF subtype, or ruxolitinib starting dose. Disclosures: Harrison: Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Kiladjian:Novartis: Honoraria; Celgene: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; Aop-Orphan: Speakers Bureau. Niederwieser:Novartis: Speakers Bureau. Passamonti:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Waltzman:Novartis: Employment. Hollaender:Novartis Pharma AG: Employment. Hunter:Incyte Corporation: Employment, Equity Ownership. Levy:Incyte Corporation: Employment, Equity Ownership. Knoops:Novartis: Consultancy. Cervantes:Bristol-Myers-Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi:Novartis: Honoraria. Barosi:Novartis: Consultancy.

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Phase 1b Dose Escalation Study Of Oral Quisinostat, a Histone Deacetylase Inhibitor (HDACi), In Combination With Velcade (Bortezomib) and Dexamethasone For Patients With Relapsed Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v122.21.1932.1932 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1932-1932 ◽

Cited By ~ 1

Author(s):

Philippe Moreau ◽

Thierry Facon ◽

Cyrille Touzeau ◽

Lotfi Benboubker ◽

Martine Delain ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Level ◽

Overall Response Rate ◽

Response Rate ◽

Maximum Plasma ◽

Synergistic Activity ◽

Employment Equity ◽

Overall Response ◽

Clinical Observations ◽

Equity Ownership

Abstract Background HDACi inhibits aggresome function by acetylation of the tubulin-dynein complex that transports unfolded proteins via aggresomes to lysosomes for degradation, thereby serving as a mechanism for reversal of resistance to proteasome inhibitors. In vivo data have shown that quisinostat, a new oral pan HDACi, has a synergistic activity with bortezomib in preclinical models of MM. Methods Patients were treated with: quisinostat (Q) at escalated doses from 6 to 8 to 10 to 12 mg on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q+V+D). The secondary endpoints included safety, overall response rate, and pharmacodynamics and pharmacokinetics. Results The study has completed enrollment and eighteen patients with relapsed MM (3, 3, 6, and 6 in the 6, 8, 10 and 12 mgQ+D+V cohorts, respectively) were enrolled: 56% male; median age of 69 (range 50-82) years; all subjects received 1 to 3 prior lines of therapy (39% received 1, 50% received 2 and 11% received 3 prior lines) and half of the patients were previously exposed and sensitive to bortezomib. To date, 17 out of 18 patients (94%) discontinued treatment, among which 5 completed 11 cycles of therapy. One patient is currently ongoing. At the highest dose level (i.e., 12 mg), 2 of 6 (33%) patients experienced dose-limiting toxicity (DLT): QTc prolongation and atrial fibrillation. The MTD was therefore established at 10 mg Q for the Q+V+D regimen. Quisinostat oral absorption was rapid, with maximum plasma concentrations achieved approximately between 1 and 3 hours after drug intake. The estimated effective half-life was between 2.5 to 15 hours. Quisinostat Cmaxand AUC were comparable to previous clinical observations and increased approximately proportional with increased dose. VELCADE exposure was in line with previous clinical observations. Most common (≥15% of patients) drug related adverse events were asthenia (56%), thrombocytopenia (56%), diarrhea (44%), oedema peripheral (39%), peripheral sensory neuropathy (39%), constipation (33%), insomnia (28%), neuralgia (28%), vomiting (28%) and nausea (28%); most of them were grade 2 or lower in toxicity. The most common (≥10% of patients) grade ≥3 drug related events included thrombocytopenia (39%), QT prolongation (11%), asthenia (11%) and insomnia (11%). Dose reduction for myelosuppression (thrombocytopenia ≥G3) was required for VELCADE in 4 patients in the 10 and 12 mg cohorts. Quisinostat dose reductions were required for asthenia G2 and G3 in 2 patients (dose level 8 and 10mg). The overall response rate was 88.2% (15 of 17 patients, 95% CI: 63.6% to 98.5%), including 1 complete response, 3 very good partial responses, and 11 partial responses. The median duration of response was 6.8 months, ranging between 2.8 and 19.6 months. The observed pharmacokinetic profiles of quisinostat and bortezomib were in line with historical data. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusion Preliminary results indicate that the MTD is 10 mg quisinostat in combination with standard doses of VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma with a high response rate and has an acceptable safety profile. Disclosures: Moreau: Janssen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Facon:Janssen: Consultancy; Millennium: Consultancy; Celgene: Consultancy. Benboubker:Celgene: Consultancy. Badamo-Dotzis:Quintiles: Employment. Phelps:Janssen: Employment, Equity Ownership. Doty:Janssen: Employment. Smit:Janssen: Employment, Equity Ownership. Fourneau:Janssen: Employment, Equity Ownership. Forslund:Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. Leleu:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.

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The economic and clinical costs of chronic kidney disease following radical and partial nephrectomy in the management of small renal masses.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.353 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 353-353

Author(s):

S. L. Chang ◽

L. E. Cipriano ◽

L. C. Harshman ◽

B. I. Chung

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Health Outcomes ◽

Partial Nephrectomy ◽

Base Case ◽

Small Renal Masses ◽

Renal Masses ◽

Lifetime Horizon ◽

Life Years ◽

The Impact

353 Background: Postoperative chronic kidney disease (PCKD), defined as a glomerular filtration rate of < 60mL/min/1.73m2, is a recognized adverse outcome after extirpative therapy for small renal masses (SRM, ≤ 4cm). We quantified the long-term economic and clinical costs of PCKD following radical and partial nephrectomy for the management of SRM. Methods: Using a Markov model, we evaluated open and laparoscopic approaches for radical and partial nephrectomy in the treatment of SRMs. The base case was a 65-year old healthy individual with a unilateral SRM and normal renal function. We used a 3-month cycle length, lifetime horizon, societal perspective, and 3% discount rate. The costs, quality of life adjustments, and transition probabilities were estimated from the literature, Medicare, and expert opinion. Health outcomes were measured in quality-adjusted life-years (QALY) gained and costs in 2008 U.S. dollars. The model was tested with sensitivity analyses. Results: The average discounted lifetime outcomes are listed in the Table. There were minimal differences between the open and laparoscopic approaches. PCKD led to a substantial increase costs and decrease in health outcomes. The impact of PCKD was indirectly associated with age. Conclusions: Partial nephrectomy provides cost-savings and improved health outcomes compared to radical nephrectomy in the management of patients with SRMs. Both procedures incur significant economic and clinical costs due to the development of PCKD. A discussion about the potential for PCKD should be incorporated into the informed consent for surgical treatment of SRMs. [Table: see text] No significant financial relationships to disclose.

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