Dueck, Amylou C.

PURPOSE: Patients' concerns regarding clinical trial (CT) participation include apprehension about side effects, quality of life (QoL), financial burden, and quality of care. METHODS: We prospectively evaluated the experience of patients with multiple myeloma or lymphoma who were treated on CTs (CT group, n = 35) versus patients treated with standard approaches (non-CT group, n = 88) focusing on QoL, financial burden of care, and patients' perception of quality of care over a 1-year period. RESULTS: There were no significant differences in any of the patient-reported outcomes in CT versus non-CT groups. We observed an initial decline in overall QoL in the first 3 months across both groups, driven primarily by physical and functional well-being. QoL gradually improved and was above baseline by month 12. Patients reported highest improvement in the functional well-being subdomain. Patients in both groups reported high satisfaction with the quality of care received, and there were no differences in overall satisfaction, communication with team, or access to care. At baseline, 16%-19% of patients reported financial burden, which increased to a peak of 33% in the CT group and to 49% in the non-CT group over the course of 1 year. There was no significant difference in financial burden in the two groups overall. Most of the patients reported getting all the care that was deemed medically necessary in both groups. However, a significant proportion of patients reported having to make other kinds of financial sacrifices because of their cancer (CT group: 33% of patients at baseline and 21%-40% over 1 year; non-CT group: 19% at baseline and 25%-36% over 1 year). CONCLUSION: Patients treated on CTs reported comparable QoL and quality of care with the non-CT group. A high proportion of patients reported financial burden over time in both groups. Our findings can serve as a guide to educate patients regarding CT participation and highlight the need to address the significant financial burden experienced by patients with cancer.

Abstract Background: Quality of life (QOL) in breast cancer patients (pts) can be greatly impacted by initial treatment and ongoing therapy, particularly if side effects and symptoms are not well tolerated. The PALLAS trial investigated whether the addition of 2 years of palbociclib (palbo) to adjuvant endocrine therapy (ET) improved invasive disease-free survival (iDFS) over adjuvant ET alone. We report on the main patient-reported outcome (PRO) quality of life (QOL) and symptom severity results of this trial by treatment arm. Methods: PALLAS is an ongoing multicenter, open label phase 3 trial that enrolled hormone receptor positive, HER2-negative, stage II-III breast cancer patients at 406 cancer centers across 21 countries. Patients were randomly assigned (1:1) to either 2 years of palbo (125mg/day, 3 weeks on 1 week off) plus ongoing provider or patient-choice adjuvant ET (palbo+ET) versus ongoing ET alone. The primary study endpoint was iDFS. Treatment with palbo in all pts stopped at the time of the second interim analysis (5/2020) due to futility; all pts then moved to follow up. The PRO analyses were triggered for completion after awareness of the pre-specified 469 iDFS cases in November 2020. Eight PRO endpoints were measured serially (i.e., day 1 of each monthly cycle for the first 3 months, then every 3 months for the first 2 years, and once at year 3). The endpoints were the EORTC QLQ-C30 global health status/QOL score, the Brief Fatigue Inventory score, the modified Brief Pain Inventory severity and pain interference scores, the EORTC QLQ-BR23 alopecia score, and the Breast Cancer Prevention Trial hot flash symptoms, vaginal problems, and musculoskeletal pain scores. Linear mixed models compared the average difference between arms across time points during the initial 2-year treatment period adjusting for cycle 1 day 1 (C1D1) PRO scores, demographic and clinical variables. The average differences between arms (palbo+ET vs ET alone) and the two-sided (1-[0.05/8]) x 100% confidence intervals, adjusted for multiple comparisons, were calculated. Analysis of covariance compared the average between-arm differences by endpoint at 3 years. Results: The PRO intention to collect population included 4688 (81%) of the overall trial pts, and was clinically and demographically representative of the remaining 1073 pts. Each analysis population, with measures at C1D1 and at least 1 post-C1D1 assessment for each PRO endpoint, comprised ≥ 89% of the 4688 pts and the proportions were similar between arms. After adjustment for baseline covariates, on average, no clinically important differences between arms were observed for any of the eight endpoints over the 2 year treatment period (Table 1). All effect sizes were below the pre-specified 0.2 threshold. These PRO results were similar at the 3 year time point. Conclusions: No clinically significant differences in either patient-reported QOL or symptom severity were found, on average, between participants in the two PALLAS treatment arms while either taking palbo+ET or ET alone, or after study-wide termination of palbo. In general, the addition of palbociclib in the adjuvant breast cancer setting did not contribute to increased symptom burden within this survivorship population. Further analyses will examine the relationship between PROs and treatment discontinuation by arm and study time point. Support: AFT, Pfizer, https://acknowledgments.alliancefound.org Table 1.Results of the Patient-Reported QOL and Symptom Severity Analyses Between the Two Treatment Arms During the First 2 Years of PALLASPRO Endpoint *Palbo + ET Adjusted average score (95% CI)ET alone Adjusted average score (95% CI)Average Difference + (Palbo + ET vs ET alone)[99.38% CI] Clinically ++ Important DifferenceEORTC QLQ-C30 Global Health Status/QOL71.7 (71.2, 72.2)74.0 (73.5, 74.5)-2.3 (-3.3, -1.4)**NoBrief Fatigue Inventory Score2.3 (2.2, 2.3)2.1 (2.0, 2.1)0.2 (0.1, 0.3)NoModified Brief Pain Inventory - Severity Score2.3 (2.2, 2.3)2.4 (2.4, 2.5)-0.2 (-0.3, -0.1)NoModified Brief Pain Inventory - Interference Score1.7 (1.6, 1.7)1.7 (1.6, 1.7)0.0 (-0.1, 0.1)NoEORTC QLQ-BR23 Alopecia1.4 (1.4, 1.4)1.3 (1.3, 1.3)0.1 (0.1, 0.1)NoBreast Cancer Prevention Trial - Hot Flash Symptoms1.2 (1.2, 1.3)1.2 (1.2, 1.3)0.0 (-0.1, 0.1)NoBreast Cancer Prevention Trial - Vaginal Problems0.8 (0.8, 0.8)0.8 (0.7, 0.8)0.0 (0.0, 0.1)NoBreast Cancer Prevention Trial - Musculoskeletal Pain1.2 (1.2, 1.2)1.3 (1.3, 1.3)-0.1 (-0.2, 0.0)No* For the EORTC QLQ-C30 Global Health Status/QOL subscale, higher scores indicate better QOL. For all other PRO endpoints, higher scores indicate worse symptom levels. ** The lower bound of the one-sided CI (adjusted for multiple comparisons) was -3.3. Because the lower limit is greater than the pre-specified non-inferiority margin of -3.44, non-inferiority of palbo+ET relative to ET-alone was concluded. The non-inferiority margin corresponds to a 0.2 SD in the EORTC QLQ-C30 global health/QOL score. +The average difference was adjusted for the following baseline covariates: Cycle 1 day 1 score, region (if applicable), age category, first adjuvant ET, race, ethnicity, N-stage, T-stage, histological grade, PgR, prior chemotherapy, ECOG Performance Status. ++Based on each instrument’s published clinically relevant cut-offs, if available. After calculating Cohen’s d treatment effect sizes, (i.e. by dividing the average difference by the ET-alone arm standard deviation from cycle 1 day 1), all effect sizes were below the pre-specified 0.2 threshold, and would not be considered clinically important. Citation Format: Michelle Joy Naughton, David Zahrieh, Michael Gnant, Nicholas Zdenkowski, Julie Lemieux, Jun J Mao, Vesna Bjelic-Radisic, Eileen Shinn, Marija Balic, Christoph Thomssen, Jane Neisel, Manuel Ruiz-Echarri, Sibylle Loibl, Claudine Isaacs, David Cameron, Fernando Manuel Henao Carrasco, Matthew Goetz, Viktor Wette, Gustavo Werutsky, Hope Rugo, Marcus Vetter, Ling-Ming Tseng, Kathy Miller, Florian Fitzal, Juan Miguel Gil Gil, Haeseong Park, Barbro Linderholm, Emilio Bajetta, Zoneddy Dayao, Aleix Prat, Karin Ehrhardt, Otto Metzger, Amal Arahmani, Ernest Law, Ann Partridge, Lisa Carey, Alex Zoroufy, Amylou Dueck, Dominik Hlauschek, Angela DeMichele, Erica Mayer. Quality of life and symptom severity in the PALLAS randomized trial of palbociclib with adjuvant endocrine therapy in early breast cancer (AFT-05) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-01.

Abstract Background Advances in the multidisciplinary care of hormone-receptor positive (HR+) early breast cancer (eBC) have markedly improved clinical outcomes: however, disease recurrence may still occur, particularly in patients (pts) with moderate or high-risk cancers at the time of diagnosis. The use of CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) is a standard of care for advanced breast cancer, supporting the rationale to study CDK4/6i in the eBC setting. Here we present the final protocol-planned analyses of the global phase III PALLAS trial investigating whether the addition of the CDK4/6i palbociclib (P) to adjuvant ET improves outcomes over ET alone for HR+/HER2- eBC. Methods PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III open-label trial in which pts with stage II-III HR+/HER2- eBC were randomized to receive either 2 years of P with adjuvant ET (P+ET) or ET alone. The primary endpoint is invasive disease-free survival (iDFS); secondary endpoints include distant recurrence-free survival (DRFS), locoregional recurrence-free survival (LRRFS), overall survival (OS), and safety. Mandatory biospecimen collection has supported the creation of an expansive translational science program, and long-term follow-up is planned. Revised sample size calculations required recruitment of 5600 pts in order to detect a 25% iDFS improvement in patients receiving P+ET with 85% power; this final protocol-planned analysis was planned after 469 iDFS events. Results From September 1, 2015 to November 30, 2018, 5,761 pts (median age 52 years, range 22-90) were randomized in 406 centers in 21 countries worldwide. 1,014 (17.6%) had stage IIA disease (capped) and 4,728 (82.1%) stages IIB/III. 4,754 (82.5%) had received prior (neo)adjuvant chemotherapy. After a protocol-planned 2nd interim analysis in May 2020 crossed the futility threshold, 349 P+ET pts still on active treatment stopped P and were transferred to follow-up. At the time of final analysis cutoff date (November 20, 2020), after a median follow-up of 31 months and 516 events recorded, iDFS was similar between the two arms, with 3-year iDFS of 89.3% (95% CI: 87.8-90.6%) for Palbo+ET, and 89.4% (88.0-90.7%) for ET alone (hazard ratio 0.96, 95% CI: 0.81-1.14). There was no statistically significant difference in secondary outcome endpoints. Subgroup analyses revealed no significant interactions between treatment effect and other factors (including risk category). The safety profile of P was as expected, with grade 3 or 4 neutropenia the most common side effect (safety population: 1759/2841 [61.9%] vs 11/2902 [0.4%]). Overall 42% of pts. discontinued P prior to the planned 2-year duration, 28.2% of Palbo+ET pts discontinued therapy due to adverse events, without an observed impact on survival outcomes. Conclusions Now with the full number of events, this analysis of the PALLAS trial shows that the addition of 2 years of P to ongoing adjuvant ET did not improve survival endpoints for pts with stage II-III HR+/HER2- eBC. Whether P is beneficial in the adjuvant setting for certain sub-groups of pts will be further evaluated with longer-term follow-up and by the ongoing translational science program. Support: ABCSG; AFT; Pfizer; ClinicalTrials.gov Identifier: NCT02513394; https://www.abcsg.org; https://acknowledgments.alliancefound.org Citation Format: Michael Gnant, Amylou C Dueck, Sophie Frantal, Miguel Martin, Hal Burstein, Richard Greil, Peter Fox, Antonio C Wolff, Arlene Chan, Eric Winer, Christian Singer, Kathy Miller, Marco Colleoni, Michelle Naughton, Gabor Rubovszky, Judith Bliss, Ingrid A Mayer, Guenther G Steger, Zbigniew Nowecki, Olwen Hahn, Norman Wolmark, Hope Rugo, Georg Pfeiler, Hannes Fohler, Otto Metzger, Céline Schurmans, Kathy P Theall, Dongrui R Lu, Kathleen Tenner, Christian Fesl, Angela DeMichele*, Erica L Mayer, *shared last authorship. Adjuvant palbociclib in HR+/HER2- early breast cancer: Final results from 5,760 patients in the randomized phase III PALLAS trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-07.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

TPS194 Background: Despite a growing number of treatment options for first line mCRPC, approximately 40% of patients (pts) have radiographic progression within the first year. Androgen receptor (AR) signaling inhibition increases genomic instability with double-strand DNA breaks & co-inhibition of AR & PARP induces synthetic lethality in multiple preclinical models. Homologous recombination repair (HRR) gene aberrations do not appear to be necessary for this synergy as demonstrated in a ph 2 clinical trial of abiraterone & olaparib where this combination improved radiographic progression-free survival (rPFS) in HRR-wild-type pts compared with abiraterone alone. A ph 1b trial has since shown that enzalutamide plus rucaparib has acceptable safety profile & no significant drug-drug interactions (S-DDI). Methods: CASPAR/A031902 (NCT04455750) is a ph 3 study in which 984 pts will be randomized 1:1 to enzalutamide plus rucaparib or placebo. HRR gene aberration is not required for enrollment. All pts will undergo next-generation targeted-exome sequencing from archival tumor tissue (new biopsy only required if no archival tissue available). Treatment will be continued until disease progression & crossover is not allowed. Key eligibility criteria are age ≥ 18 years, ECOG PS 0-2, biopsy-proven prostate adenocarcinoma, progressive (PSA or radiographic) disease per Prostate Cancer Working Group 3 guidelines, measurable or nonmeasurable disease per RECIST 1.1, no prior treatment for mCRPC (prior docetaxel, abiraterone, darolutamide, or apalutamide in non-mCRPC setting is allowed), no significant uncontrolled comorbidity, & no medications with S-DDI with enzalutamide/rucaparib. Hierarchical co-primary endpoints are rPFS & overall survival (OS). The OS analysis will be undertaken as a primary endpoint if the rPFS endpoint is met. For a one-sided logrank test with a type 1 error rate equal to 0.025, the study has 90% power to detect a hazard ratio (HR) of 0.71 in rPFS (median rPFS of 15 & 21 months in control & combination arms, respectively) & 80% power to detect an HR of 0.80 in OS (median OS of 32 & 40 months, respectively). Key secondary endpoints are rPFS & OS in pts with vs without pathogenic BRCA1, BRCA2, or PALB2 alterations; & differences in adverse events & quality of life (QOL) outcomes between the treatment arms. QOL assessments include Functional Assessment of Cancer Therapy–Prostate (FACT-P), Brief Pain Inventory Short Form (BPI-SF) & EQ-5D-5L. A key correlative endpoint is the sensitivity of ctDNA-based testing for alterations in HRR genes. Enrollment to CASPAR began in July 2021 & the study is available for participation to all US-NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882, U24CA196171; U10CA180888; Clovis Oncology; http://acknowledgments.alliancefound.org Clinical trial information: NCT04455750.

Abstract Background Previous literature often indicates that binary longitudinal data, such as responder analysis with patient-reported outcomes to evaluate treatment risks and benefits in cancer randomized controlled trials, need complex statistical approaches for a thorough evaluation of the treatment effect and consequently elaborated clinical design and power calculation for prospective trials. This simulated analysis aims to evaluate six common statistical techniques used for binary longitudinal data to explore the feasibility and overall functionality of these methods in comparison to more complex modeling techniques. Methods We simulated data to represent a typical clinical trial design, with dichotomous outcome, and treatment vs control group at three waves T1, T2, and T3. We evaluated five sample size conditions ranging from small to large with 1,000 replicates each. We then evaluated results from six statistical techniques (Generalized linear model [GLM] with generalized estimating equations [GEE], Generalized linear mixed model [GLMM], Logistic regression, Cochran-Mantel-Haenszel [CMH], Chi-square, and Fisher’s Exact test) and their ability in detecting difference between treatment groups under different conditions. Results While less elaborated models always achieved convergence, the convergence rate of GLMM with unstructured covariance matrix ranged from 7–43%. The proportion of detected significant differences between control and treatment expectedly increased with the increasing of the sample size but remained somewhat similar across modeled outcome and sample size scenarios. Conclusions Overall results indicated that, with careful consideration, straightforward modelling approaches which require less assumptions in design and power calculation are sufficient to ensure meaningful, adequately powered, evaluation of treatment effect.

Background In clinical trials and clinical practice, patient-reported outcomes are almost always assessed using multiple patient-reported outcome measures at the same time. This raises concerns about whether patient responses are affected by the order in which the patient-reported outcome measures are administered. Methods This questionnaire-based study of order effects included adult cancer patients from five cancer centers. Patients were randomly assigned to complete questionnaires via paper booklets, interactive voice response system, or tablet web survey. Linear Analogue Self-Assessment, Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, and Patient-Reported Outcomes Measurement Information System assessment tools were each used to measure general health, physical function, social function, emotional distress/anxiety, emotional distress/depression, fatigue, sleep, and pain. The order in which the three tools, and domains within tools, were presented to patients was randomized. Rates of missing data, scale scores, and Cronbach’s alpha coefficients were compared by the order in which they were assessed. Analyses included Cochran–Armitage trend tests and mixed models adjusted for performance score, age, sex, cancer type, and curative intent. Results A total of 1830 patients provided baseline patient-reported outcome assessments. There were no significant trends in rates of missing values by whether a scale was assessed earlier or later. The largest order effect for scale scores was due to a large mean score at one assessment time point. The largest difference in Cronbach’s alpha between the versions for the Patient-Reported Outcomes Measurement Information System scales was 0.106. Conclusion The well-being of a cancer patient has many different aspects such as pain, fatigue, depression, and anxiety. These are assessed using a variety of surveys often collected at the same time. This study shows that the order in which the different aspects are collected from the patient is not important.

Abstract Background Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. Methods Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. Results Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). Conclusion Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

Abstract The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.