bluuebunny/crossref_metadata_2025 huggingface dataset:
Quality of life (QOL) predicts for progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib compared to interferon-alpha (IFN-α)
Authors: Cella D. , Li J. Z. , Cappelleri J. C. , Bushmakin A. , Charbonneau C. , Kim S. T. , Chen I. , Michaelson M. D. , Motzer R. J.
Published: March 2020

6594

Background: In a recent international, randomized phase III trial, sunitinib malate, an oral multitargeted receptor tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3 with both antitumor and antiangiogenic effects, was associated with statistically superior clinical efficacy and superior health-related QOL vs. IFN-a as first-line therapy in patients with mRCC (Motzer et al, Proc ASCO 2006;24:2s [Abstract LBA3]). Here we report a substudy of baseline QOL variables predicting PFS. Methods: 750 mRCC patients were randomized 1:1 to receive either sunitinib 50 mg orally once daily in repeated 6-week cycles (4 weeks on treatment followed by 2 weeks off) or IFN-a (9 MU via subcutaneous injection 3 times weekly). QOL was measured by the Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index's Disease-Related Symptoms subscale (FKSI-DRS), and the patient self-rated overall health state (EQ-VAS) from the EuroQol Group's EQ-5D self-report questionnaire. For all QOL endpoints, higher scores indicated better outcomes (better QOL or fewer symptoms). Cox proportional-hazards model was used to test which baseline QOL variables predict PFS while controlling for other baseline demographic and clinical factors as well as treatment. Because the three QOL scores are correlated (r=0.61–0.69), three separate univariate models were fitted. Results and Conclusions: All three baseline QOL variables were predictive of PFS: better baseline FACT-G, FKSI-DRS and EQ-VAS scores were associated with longer PFS. When QOL and other baseline variables were controlled in the models, the superior treatment effect of sunitinib on PFS remained robust and large (See the table below).

[Table: see text]
E-tablets to collect research-quality patient-reported data
Authors: Abernethy A. P. , Herndon J. , Day J. , Hood L. , Wheeler J. , Patwardhan M. B. , Shaw H. S. , Lyerly H. K.
Published: March 2020

6609

Introduction: Programmed wireless notebook computers (e-tablets) can collect review of systems (ROS) data at point of care. Patients complete surveys in the clinic waiting area; a report is generated for the subsequent clinical visit. Are e-tablets a feasible, acceptable method for collecting data directly from patients in an academic cancer clinic? Can they reliably collect other survey data? Methods: We used PACE e-tablets (SOS, Inc.) to administer Functional Assessment of Cancer Therapy (FACT)-G, FACT-B, MD Anderson Symptom Inventory (MDASI), FACIT-Fatigue, and Self Efficacy instruments, in addition to the PACE Patient Care Monitor (PCM) ROS survey. Participants were 66 breast cancer patients in Duke Breast Cancer Clinic. At 4 visits in 6 months, participants completed all electronic and 1 paper survey. Subscales were compared using paired t-tests. Patients completed an electronic survey of satisfaction with PCM. Results: Mean age, 55 (SD 12); 77% Caucasian; 49% no college degree; 68% married; 61% metastatic cancer. Patients strongly supported e-tablets: easy to read (94%), easy to respond to questions (98%), weight of computer comfortable (87%). Satisfaction increased over time: helpful for reporting symptoms (75–88%), would recommend PCM to other patients (87–94%). 75% indicated PCM helped them remember symptoms to discuss with the clinician. Responses to paper and electronic surveys were nearly identical for 3 of 4 FACT-G, and all FACT-B, MDASI, and FACIT-Fatigue subscales (all p>0.31). Responses on FACT-G Social Wellbeing and 4 Self Efficacy subscales differed from paper to electronic (all p<0.006, all electronic scores poorer). Conclusions: Patients are satisfied with e-tablets. E- tablets furnish comparable data to those collected by paper on nearly all scales tested. PCM offers a valid, feasible method for collecting research-quality, clinically relevant data from patients in outpatient academic oncology.

No significant financial relationships to disclose.
Incidence and prevalence of brain metastases among patients with advanced breast cancer in a United States managed-care population
Authors: Pelletier E. M. , Amonkar M. M. , Shim B.
Published: March 2020

6624

Background: There continues to be uncertainty about the extent of the breast cancer (BC) population afflicted with secondary brain metastases (BM). This study estimated the incidence and prevalence of BM among patients with advanced BC in a US-based population. Methods: Female BC patients diagnosed with secondary BM between 1/2002 and 12/2004 and with a brain or head diagnostic test within 30 days of the BM diagnosis were identified from a nationally representative private payer database (PharMetrics, Inc.). The date of the first BM diagnosis served as the index date. A 1-year look-back period was used to identify patients with a diagnosis of BC and those with and without a history of BM. Patients were required to have continuous health plan enrollment for 1 year prior to and at least 1 month following the index date. Patients aged <18 years, and those aged 65+ and not in a Medicare Risk plan were excluded. The denominator for incidence and prevalence calculations included all patients with diagnosed advanced BC during the study period. A death proxy algorithm was used to estimate the mortality rate. Results: 779 incident and 995 prevalent BM patients were identified; mean age of each cohort was 53 years. In the 1 year prior to the index diagnosis, 73.6% of incident patients were treated with chemotherapy and 25.0% received radiation therapy; <10% of patients had a lumpectomy, mastectomy, or lymph node dissection. About 22% of incident patients died during the follow-up period, an average of 158 days (95% CI=131.1, 183.9) from the index BM diagnosis. From 2002–2004, 8,518 advanced BC patients were identified, resulting in a BM incidence rate of 9.1% (95% CI=8.5%, 9.8%). During this same period, the prevalence of BM was found to be 11.7% (95% CI=11.0%, 12.4%), with rates increasing by year. On average, the first diagnosis of BM occurred 123 days (95% CI=106.9, 139.3) following the BC diagnosis. Conclusions: Secondary BM is a common occurrence among advanced BC patients. The BM incidence rate is in the range (5–20%) of previously published studies. The prevalence of BM was 28% higher than the incidence and increased over time. This increasing frequency suggests an unmet need that could be filled with newer treatments that improve BC outcomes, including the prevention or delay of BM.

No significant financial relationships to disclose.
Use of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in chronic phase (CML-CP)
Authors: Atallah E. L. , Kantarjian H. , O'Brien S. , Jones D. , Borthakur G. , Nicaise C. , Cortes J.
Published: March 2020

7005

Background: Dasatinib (formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with imatinib (im) resistant/intolerant CML-CP, the present phase II trial was designed to study previously untreated CML-CP pts treated with dasatinib. The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio =0.05% by qPCR) at 12 months (mo). Methods: All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily or a 100 mg-once-daily schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Of the 31 pts enrolled between 11/05 and 12/06; 52% were female; median age was 41 years (range 18–76). At 3 mo, complete hematologic response (CHR) and major cytogenetic response both occurred in 21 (81%) of 26 evaluable pts and complete cytogenetic response (CCyR) in 19 (73%) pts. After 6 mo of therapy, 20/21 (95%) evaluable pts had achieved CCyR. This compares favorably with a CCyR at 6 mo of 54% with im 400 mg/day and 85% with im 800 mg/day, in historical data of similar patients treated in studies at MD Anderson. At 9 mo, 4/15 (27%) evaluable pts had achieved a major molecular response. The most common non-hematologic adverse events (AE) included dyspnea (8 pts), fatigue (7 pts), muscle pain (6 pts), and headache (5 pts) and were predominantly grade (gr) 1–2. Pleural effusion occurred in only 3 pts (gr 1–2 in all). Grade 3–4 hematologic toxicity (transient) included anemia in 4 pts, neutropenia in 7 pts, and thrombocytopenia in 4 pts. With a median duration of therapy of 10 mo, 13 pts required transient treatment interruption, 9 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. The actual median daily dose for all pts was 100mg. No difference in AEs has been observed between dose schedules. Conclusions: Rapid, complete cytogenetic responses to dasatinib 100 mg/day have been observed in a high percentage of patients with previously untreated CML- CP. Accrual to this trial continues.

No significant financial relationships to disclose.
Weekly docetaxel versus docetaxel/gemcitabine in elderly/poor performance status (PS) patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC): Randomized phase III trial of the Minnie Pearl Cancer Research Network
Authors: Greco F. A. , Spigel D. R. , Burris H. A. , Shipley D. L. , Farley C. , Gandhi J. , Houston G. A. , Hainsworth J. D.
Published: March 2020

7534

Background: Standard treatment for pts with good PS stage IIIB/IV NSCLC currently includes a two-drug platinum-based chemotherapy regimen. Optimum treatment for elderly and/or poor PS pts is less well defined, with some studies showing comparable efficacy/decreased toxicity with single agent treatment. In this randomized phase III trial we compared single agent weekly docetaxel with the combination of docetaxel/gemcitabine. Methods: Between 8/01 and 3/06, 350 pts were enrolled from 39 sites. Eligibility: previously untreated stage IIIB/IV NSCLC; age = 65 years and/or ECOG PS2; measurable disease; no active CNS metastases; adequate kidney, liver, marrow function; informed consent. Pts were randomized to receive docetaxel (36 mg/m2 IV days 1, 8, 15; repeated every 28 days) or docetaxel (30 mg/m2)/gemcitabine (800 mg/m2) both given days 1, 8, 15 of a 28-day cycle. Pts were reevaluated after 8 weeks; responders continued treatment for 6 cycles or until disease progression. Accrual of 330 evaluable pts allowed detection of improvement in 1-year survival from 25% (expected with weekly docetaxel) to 40% (significance level 0.05, power 0.8). Results: Clinical features of pts receiving docetaxel/gemcitabine (n=174) vs. weekly docetaxel (n=171) were similar; 19% were ECOG PS2, and 38% were > 75 years old. After a median follow-up of 22 months, there were no differences between docetaxel/gemcitabine vs weekly docetaxel in median survival (5.6 vs. 5.1 months; p=0.65) or 1-year survival (26% vs. 24%). TTP was prolonged with docetaxel/gemcitabine vs. docetaxel (4.8 months vs. 2.9 months; p=0.0004). Response rates: docetaxel/gemcitabine 25%; docetaxel 17%. Both regimens were well tolerated by most pts; grade 3/4 neutropenia, thrombocytopenia, and anemia were more frequent with docetaxel/gemcitabine. Conclusions: These two regimens have similar efficacy in these elderly/poor PS pts; weekly docetaxel produced less myelosuppression. However, these results in this relatively unselected community-based population emphasize the need for novel treatment approaches.

No significant financial relationships to disclose.
A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342
Authors: Herbst R. S. , Chansky K. , Kelly K. , Atkins J. N. , Davies A. M. , Dakhil S. R. , Albain K. S. , Kim E. S. , Crowley J. J. , Gandara D. R.
Published: March 2020

7545

Background: Randomized clinical trials have failed to show a survival benefit for small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors plus chemotherapy in unselected patients with metastatic NSCLC. In contrast, pilot trials of EGFR targeted antibodies plus chemotherapy have suggested enhanced anti-tumor activity. This randomized phase II selection trial was designed to select a cetuximab-chemotherapy regimen for future evaluation in a phase III setting. Methods: Untreated patients (pts) with advanced stage NSCLC were randomized to receive paclitaxel (P) 225 mg/m2 and carboplatin (Cb) AUC=6 every 3 weeks plus concurrent cetuximab (C) 400 mg/m2 loading dose followed by 250 mg/m2, weekly for 4 cycles followed by maintenance C or sequential PCb for 4 cycles followed by C. Treatment was continued until disease progression. Eligible patients were required to have stage IIIB (pleural effusion) or IV (without brain metastases) disease, a performance status of 0–1 and adequate organ function. The primary endpoint was overall survival. The regimen with superior median survival would be considered for further evaluation provided it met a 10-month minimum. Given a true hazard ratio of 1.3, the probability of correctly choosing the superior arm would be > 90%. Results: From July 2004 to June 2005, 242 eligible pts were enrolled onto the study, Final results are described below: Conclusions: Both regimens met efficacy criterion for continued evaluation though the concurrent regimen of PCb + C, had numerically higher survival, and was chosen for further study. Some toxicities were significantly increased with concurrent therapy. A phase II trial of PCb + Cetuximab + Bevacizumab is ongoing (SWOG 0536) in anticipation of a phase III trial. Molecular correlative studies of the EGFR signaling pathway including EGFR IHC, FISH and mutation analysis are underway.

No significant financial relationships to disclose.

[Table: see text]
A front-line window of opportunity phase II study of sorafenib in patients with advanced non-small cell lung cancer: A North Central Cancer Treatment Group study
Authors: Adjei A. A. , Molina J. R. , Hillman S. L. , Luyun R. F. , Reuter N. F. , Rowland K. M. , Jett J. R. , Mandrekar S. J. , Schild S. E.
Published: March 2020

7547

Background: Sorafenib is a multikinase inhibitor with single-agent activity in previously treated NSCLC. In an effort to evaluate its single agent activity in previously untreated NSCLC, the NCCTG undertook a front-line “window of opportunity” study. Materials and Methods: Patients with stage IIIB (pleural effusion) or stage IV NSCLC received sorafenib dosed at 400 mg BID continuously, with a cycle defined as 4 weeks. Patients were evaluated weekly during the first 2 cycles with those who progressed rapidly going on to receive standard chemotherapy. Based on a two-stage Fleming design, if only at most 1 confirmed response was observed in the first 20 patients enrolled to stage I, the regimen would be considered ineffective. If 2 or more responses were observed, the study would proceed to stage 2 and accrue an additional 22 patients. If 5 or more confirmed responses were observed, the regimen would be recommended for further testing. Results: The study did not meet the stage I efficacy criteria (only 1 confirmed partial response in the first 20 patients) and was permanently closed after enrolling 25 evaluable patients [15 females, 10 males; 4 stage IIIB, 21 stage IV; median age 67 (45–85)]. 2 patients are still receiving treatment (14 and 15 months). No grade 3 or higher hematologic adverse events were observed. Thirteen (52%) patients had a grade 3 non-hematologic adverse event with fatigue (20%), diarrhea (8%), and dyspnea (8%) being the most common. There was one grade 4 pulmonary hemorrhage. A total of 3 (12%) PRs; and 7 (28%) SD were observed in the 25 patients 7 (28%) patients were progression- free at 24 weeks. Median survival and median time to progression were 8.8 and 2.9 months respectively. Conclusion: While the pre- specified efficacy endpoints were not met, the objective response rate of 12% and median survival of 8.8 months suggest that single agent sorafenib has activity similar to two-drug combinations. The feasibility and utility of the “window of opportunity” design in estimating the activity of novel compounds was demonstrated. Finally, the single-agent activity of sorafenib argues for combination studies with standard chemotherapy agents.

No significant financial relationships to disclose.
Toxicity and survival by sex in patients with advanced non-small cell lung carcinoma (NSCLC) on modern Southwest Oncology Group (SWOG) trials
Authors: Albain K. S. , Unger J. , Gotay C. C. , Davies A. M. , Edelman M. , Herbst R. S. , Kelly K. , Williamson S. , Wozniak A. J. , Gandara D. R.
Published: March 2020

7549

Background: The older lung cancer clinical trial literature suggests that women have better survival than men, possibly due to sex-related changes in drug metabolism based on estrogen levels. A detailed analysis of this issue has not been conducted in the modern chemotherapy era. Thus, the SWOG Lung Committee analyzed outcomes in recent trials, with the hypotheses that either sex-specific toxicity profiles and/or age (as a surrogate for estrogen level) may explain outcome differences. Methods: A data base of eligible patients with complete toxicity data enrolled on 6 consecutive SWOG phase II or III advanced stage NSCLC trials was formed. Treatment was platin-based, plus either gemcitabine, vinorelbine, or a taxane. Toxicities were categorized by type, number and grade with alpha=0.01 (multiple comparisons). Kaplan-Meier survival estimates and Cox multivariate models were computed (alpha=0.05), plus exploratory age by sex interaction analyses. Results: There were1,324 patients (36% women). No difference by sex was found in either maximum toxicity grade, number of toxicities, or specific toxicity types, except for marginally more severe or worse metabolic (12% vs 9%, p=0.02) and life- threatening or worse neurologic (2% vs 1%, p=0.04) toxicities in women. Median, 1- and 2-year survivals were significantly better for women (11 mos, 46%, 19%) vs men (8 mos, 35%, 13%). After adjustment for prognostic factors, women had 14% reduced risk of death (HR 0.86; 95% CI: 0.75, 0.98; p=0.02). The exploratory age by sex cutpoint analysis found women age 60 or older had better survival (11 vs 8 mos, p=0.006), whereas survival was similar by sex for those under age 60. No other age cutpoint was significant. Conclusions: Women with advanced NSCLC survive longer than men after adjustment for other prognostic factors in the modern chemotherapy era. There was no difference in toxicity profile by sex to explain this finding. The survival benefit for women appeared limited to patients age 60 and older, suggesting that estrogen levels may interact with the efficacy of current chemotherapy prescriptions or other as yet undefined factors. This finding, if validated, could be potentially exploited in designing new therapies.

No significant financial relationships to disclose.
CALGB 30306: A phase II study of cisplatin (C), irinotecan (I) and bevacizumab (B) for untreated extensive stage small cell lung cancer (ES-SCLC)
Authors: Ready N. , Dudek A. Z. , Wang X. F. , Graziano S. , Green M. R. , Vokes E. E.
Published: March 2020

7563

Background: VEGF is expressed in 80% of SCLC. Combining chemotherapy with B is effective in advanced non-small cell lung, breast and colon cancers. Methods: This was a phase II study of C 30 mg/m2 and I 65 mg/m2 days 1 and 8 plus B 15 mg/kg day 1 every 21 days for up to 6 cycles in patients with untreated ES-SCLC, PS 0–2, and adequate organ function. Eligibility required no significant bleeding, uncontrolled hypertension, brain mets or other risk factors for B therapy. An initial safety cohort of ten patients was closely followed for unexpected/severe toxicities. Pretreatment blood was collected for biomarker analysis. Statistical design: primary endpoint 12 mo survival rate > 57% (median survival ≥15 mo). Results: 72 pts were enrolled from 3/05–4/06 with one patient deemed ineligible due to diagnosis NSCLC. Demographics: 51% female; median age 62; PS 0–23%, 1–68%, 2–10%. There were no episodes of grade 3 or greater hemoptysis or other primary hemorrhagic episodes. One patient died after an embolic/thrombotic stroke bled secondarily. Other grade 3/4 toxicities included (%): anemia 5, neutropenia 23, platelets 10, hypertension 6, fatigue 12, diarrhea 17, nausea 11, bowel perforation 2, infection 14, all electrolyte 23, stroke 4, vascular access thrombosis 3. Deaths on therapy 3 (4%): pneumonitis 1, stroke 1, heart failure 1. Preliminary efficacy: CR 2 (3%), PR 42 (59%), SD 9 (13%), PD 1 (1%); ORR 62%; ORR excluding unevaluable (4%)/no data (18%): 80%; median progression free survival 7.0 mo (95% C.I. 6.2,8.0); median overall survival 10.6 mo (95% C.I. 8.5, 11.7); median follow-up 9.5 mo. Pretreatment VEGF/PDGF titers have been measured, reported to the CALGB statistics center, and will be analyzed in relation to response and survival outcomes. Conclusions: Although ES-SCLC often has bulky central disease there was no clinically significant hemoptysis. All patients will be at least 12 months from initiation of therapy by 5/07, and mature response and survival data will be presented.

No significant financial relationships to disclose.
Phase II study of the efficacy and safety of intravenous (IV) AVE0005 (VEGF Trap) given every 2 weeks in patients (Pts) with platinum- and erlotinib- resistant adenocarcinoma of the lung (NSCLA)
Authors: Massarelli E. , Miller V. A. , Leighl N. B. , Rosen P. J. , Albain K. S. , Hart L. L. , Melnyk O. , Sternas L. , Ackerman J. , Herbst R. S.
Published: March 2020

7627

Background: AVE0005 (VEGF Trap) is a recombinant fusion molecule of the human VEGF receptor extracellular domains and the Fc portion of human IgG1. Methods: This is an open-label, single arm, multi-center trial employing a Simon 2-stage design. A total of 94 pts are planned. Three responses in the first 37 evaluable pts are required to progress to the second stage. IV AVE0005 (VEGF Trap) 4.0 mg/kg is given every 2 weeks to pts with platinum- and erlotinib-resistant, locally advanced or metastatic NSCLA. Other eligibility requirements include prior treatment with at least two cancer drug regimens in the advanced disease treatment setting, measurable disease, and ECOG performance status (PS) =2. Exclusions include squamous-cell lung cancer, prior treatment with a VEGF or VEGF receptor inhibitor with the exception of bevacizumab, history of brain metastasis, significant bleeding diathesis. End points are objective response rate, safety profile, duration of response, progression-free survival, overall survival and quality of life. Results: The study is ongoing and response and safety data are available for 33 pts (median age=60; males/females=14/19; ECOG PS 0/1/2=6/26/1 pts). A total of 132 cycles have been administered (median=4). Most common reason for withdrawal was progressive disease. Grade 3–4 treatment emergent adverse events (TEAEs) included (pts/percent) dyspnea (5/15%), hypertension and non-cardiac chest pain (3 pts each/9 %) fatigue (2/6 %), and anxiety, epistaxis, nausea, bone pain, proteinuria, febrile neutropenia, pneumonia, pulmonary embolism, and renal pain (1 each/3%). No grade 3 or greater hemoptysis has occurred. Two partial responses (PRs) have been reported to date. Conclusions: AVE0005 (VEGF Trap) 4 mg/kg IV has shown to be generally well tolerated; no significant hemoptysis has been seen to date. Single agent activity has been observed in this heavily treated population; interim futility analysis is awaited. The safety and preliminary activity profile supports further investigation with other targeted agents and cytotoxic chemotherapy.

[Table: see text]
Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): JCOG0207
Authors: Tsukada H. , Yokoyama A. , Nishiwaki Y. , Shinkai T. , Harada M. , Ando M. , Shibata T. , Ohe Y. , Tamura T. , Saijo N.
Published: March 2020

7629

Background: Platinum-based chemotherapy is currently recommended as the standard approach for pts with advanced NSCLC. However prospective clinical trials specifically designed for elderly pts demonstrating the P benefit are still lacking. Therefore, we conducted a phase III trial to determine whether the addition of P to single agent-chemotherapy for elderly NSCLC pts could improve survival. Methods: Eligibility criteria included; chemotherapy-naive; stage III/IV NSCLC; age=70 and PS 0–1. Pts were randomized to receive either DP or D with minimization method balancing site, age (=74/=75) and stage (III/IV), and both regimens were given every 4 weeks. DP comprised D (20 mg/m2) and P (25 mg/m2) iv on days 1, 8, 15. D comprised D (25 mg/m2) iv on the same schedule. Primary endpoint was overall survival (OS). The planned sample size was 115 pts in each arm to provide 80% power to detect 0.667 hazard ratio for DP to D in OS and 2.5% one-sided alpha. Results: Between Apr 2003 and Apr 2006, 126 pts were randomized (D/DP: 63/63). The second planned interim analysis was performed on 112 assessable pts (D/DP:56/56, median age 76, =74/=75: 39/61%, male/female: 77/23%, PS 0/1: 39/61%, III/IV: 30/70%). Maturity of information, defined proportion of interim events to the planned events, was 26% (=49/191). As the one-sided p-value(p=0.00515) of the stratified log-rank test by age and stage was not lower than the critical value for the interim analysis, the formal criterion for stopping the trial failed to meet. However the Data and Safety Monitoring Board recommended study termination and disclosure of the results based on the strong interaction (two-sided p=0.077, hazard ratios [95% C.I.] for =74/=75: 0.23 [0.09–0.62]/0.72 [0.35- 1.49]) that DP may be beneficial for subgroup of age between 70- 74. Major Grade 3–4 toxicities were (%D/DP): neutropenia 4.9/13.1, anemia 1.6/16.4, anorexia 8.3/24.2, infection 11.7/8.1, pneumonitis 1.7/1.6. TRD occurred in 1 pt in DP arm. Conclusions: The interpretation of study results is limited due to early stopping and resultant loss of statistical power. But these data indicated that =74 young elderly have no more need to evaluate tolerability and efficacy of P.

No significant financial relationships to disclose.
Update of the NCI multiinstitutional phase II trial of romidepsin, FK228, for patients with cutaneous or peripheral T-cell lymphoma
Authors: Piekarz R. , Frye R. , Wright J. , Figg W. , Allen S. , Kirschbaum M. , Zain J. , Hutchins L. , Showe L. , Fojo T. , Bates S. E.
Published: March 2020

8027

Background: The histone deacetylase inhibitors (HDIs) are a class of differentiating agents undergoing clinical testing. Like other HDIs, romidepsin (FK228) modulates expression of genes involved in cell cycle regulation and markers of differentiation in cancer cell lines, leading to induction of differentiation or apoptosis. Romidepsin has demonstrated clinical activity in patients with T-cell lymphoma. Methods: Patients with CTCL (42) or PTCL (36) were enrolled in the NCI multi-institutional trial and assigned to cohorts based on extent of prior therapy and pathology. Romidepsin is administered on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14mg/m2. Responses for patients with PTCL are measured using Cheson criteria, and CTCL using RECIST criteria. Results: Cohort one, composed of 27 patients who had previously received no more than 2 prior cytotoxic regimens of chemotherapy, has completed enrollment. Responses observed include 3 patients with CR and 7 patients with partial responses, yielding an overall response rate of 37%. Of note, responses were observed independent of stage of disease. Among 18 patients with stage IV disease, 6 patients had a complete or partial response, including 3 patients with Sézary syndrome. When including patients with greater than 2 prior cytotoxic regimens, the overall response rate was 31%. A replicate arm has been opened with the goal of confirming the response rate observed in the first cohort. Response data have not been evaluated from this arm at this time. Responses observed in 36 patients with refractory or relapsed PTCL includes 3 patients with CR and 8 patients with partial responses, comprising an overall response rate of 30%. Responses were observed independent of prior therapy, with some patients having undergone prior stem-cell transplant. Molecular endpoint analysis was performed on peripheral mononuclear cells (PBMNCs) and tumor biopsies from treated patients evaluating histone acetylation and changes in gene expression. Conclusions: Romidepsin as a single agent appears to have significant single agent activity in patients with CTCL and PTCL. Combination therapy with romidepsin may increase efficacy and should be pursued. This protocol remains open to accrual.

No significant financial relationships to disclose.
A phase I/II study of lenalidomide (Len) in combination with rituximab (R) in relapsed/refractory mantle cell lymphoma (MCL) with early evidence of efficacy
Authors: Wang M. , Fayad L. , Hagemeister F. , Neelapu S. , Bell N. , Byrne C. , Knight R. , Zeldis J. , Kwak L. , Romaguera J.
Published: March 2020

8030

Background: MCL remains a therapeutic challenge. R targets CD20 antigen on MCL cells while Len may target the microenvironment of MCL cells and enhance the ADCC activity of R. To test this hypothesis, we initiated a single-center; open label, phase I/II study. We now report the completed phase I. Methods: Eligible patients (pts) had 1–4 lines of prior therapy including prior thalidomide or R, regardless of resistance. Each cycle of treatment consisted of Len given orally daily on days 1–21 of a 28-day cycle and R 375 mg/m2 by IV infusion weekly for 4 weeks. A standard 3+3 dose escalation was used to determine MTD with Len doses at 10 mg, 15 mg, 20 mg, and 25 mg. DLT was defined as grade (G) 3 or 4 non-hematologic or G4 hematologic toxicity during the first cycle. Results: The phase I portion completed enrollment with 15 pts (4 at 10 mg, 3 at 15 mg, 6 at 20 mg and 2 at 25 mg). Thirteen pts were evaluable. Median age was 73 (62–84); median prior lines of therapy were 3 (1–4); median cycles received to date were 2 (1–7). Two DLT's occurred at 25 mg. One pt had G3 hypercalcemia. The other had G4 neutropenic fever and died of sepsis (G5) during the first cycle. Three additional pts were therefore enrolled at 20 mg. Common non-hematologic toxic events included pruritis (21 G1–2), hypercalcemia (9 G1–2, 1 G3), fatigue (9 G1–2), constipation (8 G1), diarrhea (6 G1–2), fever (6 G1–2), myalgias (4 G1–2, 1 G3) and elevated LDH (4 G1–2, 1 G3). Hematologic events included neutropenia (20 G1–2, 4 G3), thrombocytopenia (6 G1–2, 2 G3) and anemia (6 G1). There were no responses at 10 mg or 15 mg. At 20 mg after 2 cycles, 5 out of 6 pts achieved responses including 1 CR, 1 PR, 3 minor responses (MRs) and only 1 pt progressed. The 1 pt with PR went on to achieve a CR after 6 cycles. The 3 pts with MRs had tumor reductions by 43%, 40% and 38% respectively. These 3 patients with MRs continue to receive Len and might later achieve PR or CR. Conclusions: The MTD for Len with R in relapsed/refractory MCL was 20 mg, orally daily on days 1–21 of a 28-day cycle. Responses observed at 20 mg are promising with a favorable toxicity profile and are being evaluated further in an ongoing phase II study.

[Table: see text]
Schedule of bortezomib administration may be an important determinant of single-agent activity in patients with relapsed or refractory follicular (FL) lymphoma and mantle cell lymphoma (MCL)
Authors: O'Connor O. , Hamlin P. , Moskowitz C. , Straus D. , Noy A. , Wright J. , Neylon E. , MacGregor-Cortelli B. , Portlock C. , Zelenetz A.
Published: March 2020

8051

Background: We previously demonstrated the significant activity of bortezomib for the treatment of FL and MCL. The activity in MCL has been confirmed in a multi-center study leading to the recent approval by the FDA. The demonstrated activity was observed on the twice weekly schedule. Recent data using bortezomib in combination with rituximab suggested that weekly bortezomib was less toxic and possibly equally as efficacious as twice weekly bortezomib. This study does not allow a determination of weekly single agent activity alone. We sought to evaluate the single agent activity of bortezomb in FL and MCL administered on a weekly schedule. Methods: Pts with FL and MCL were treated with bortezomib at a dose of 1.8 mg/m2 weekly for 4 of 6 consecutive weeks. To date, 20 pts (12 FL, 8 MCL) have been treated on this schedule, of which 18 are assessable for response. Two pts were inevaluable: 1 pt received steroids for bronchitis (MCL); and 1 pt (FL) with grade 2 diarrhea withdraw consent making her data inaccessible. Results: The range of cycles administered was 1 to 8, with a median of 2. The weekly dosing schedule was well tolerated with 1 pt. developing neuropathy (grade 3). Fourteen pts completed at least two cycles of therapy and underwent restaging. Two pts had a PR (both FL), 8 had SD (5 FL, 3 MCL) and 4 had POD (2 FL, 2 MCL). The other 4 evaluable patients are now being restaged. Conclusions: These data suggest weekly dosing with bortezomib may not be as effective as twice weekly. Typically, bortezomib administered on the twice weekly schedule has an ORR of 30% in MCL and 50% in FL. Additionally, the frequency of pts. experiencing POD appears to be less common on the twice weekly schedule. One difference in the schedules is the dose intensity and dose density. A cycle of twice weekly bortezomib administers 1.7 mg/m2/week, while a weekly schedule administers only 1.2 mg/m2/week, a 30% difference in dose intensity and a 100% difference in dose density (1.33 × per week vs. .67 × per week). What remains unclear from a pharmacologic perspective is the relative importance of high Cmax vs high AUC exposures, and their impact on both toxicity and efficacy. These data suggest that schedule is critical in the activity of bortezomib.

No significant financial relationships to disclose.
A multicenter phase II study of erlotinib and bevacizumab in patients with metastatic melanoma
Authors: Wyman K. , Spigel D. , Puzanov I. , Hainsworth J. , Kelley M. , Krozely P. , Sturgeon D. , Sosman J.
Published: March 2020

8539

Background: Erlotinib and bevacizumab have demonstrated activity in a number of malignancies by virtue of interrupting interdependent signaling pathways thought important in tumorigenesis. Melanoma may be an appropriate target based on its expression of EGFR and VEGF. We conducted a phase II multi-institutional trial evaluating erlotinib and bevacizumab in advanced melanoma patients. Methods: Eligibility included measurable disease, ECOG PS = 0–1, adequate organ function, no more than one prior therapy for metastatic disease, and CNS metastases were allowed if limited and controlled. Patients received oral erlotinib 150 mg/day and bevacizumab 10 mg/kg IV Q 2 weeks with tumor evaluation every 8 weeks. The primary outcomes were response rate (RR), response duration, and frequency of PFS >6 months. Secondary outcomes included overall survival, safety, and tolerability. A two-stage accrual design was employed ensuring that = 3/21 patients had PFS >6 months before additional patients were accrued. Results: As of Nov 2006, 29 patients with metastatic melanoma were enrolled. A total of 23 patients were evaluable for response. The majority was male 19/29 (65%) and had a median age = 62 yrs (range 35–78 years). Fifteen of the 29 had stage M1c disease (51.7%) and 18/29 (62.1%) had a PS = 1. Ten patients (34%) had prior adjuvant therapy and 6 patients (21%) prior therapy for metastatic disease. There were 2/23 (9%) partial responses lasting < 6 months and 5/23 (22%) had stable disease lasting > 6 months. The median progression free survival of evaluable patients was 96 days (95% CI: 50 - 142 days). A total of 25 grade III toxicities were observed with the most common being rash/pruritis (n=4), pain (n=4), fatigue (n=3), hypertension (n=2) and diarrhea (n=2). Two grade IV toxicities were observed (myocardial infarction and bowel perforation) both thought to be due to bevacizumab. Conclusion: The combination of erlotinib (150 mg/day) and bevacizumab (10 mg/kg) appears potentially active in patients with metastatic melanoma with largely tolerable toxicities. Accrual of a total of 41 patients will be completed shortly.

[Table: see text]
A randomized phase II study of EMD 121974 in patients (pts) with metastatic melanoma (MM)
Authors: Kim K. B. , Diwan A. H. , Papadopoulos N. E. , Bedikian A. Y. , Camacho L. H. , Hwu P. , Johnson M. M. , Colevas A. D. , Prieto V. G.
Published: March 2020

8548

Background: EMD 121974 is a selective antagonist of avβ3 integrin, which promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells expressing avβ3 integrin. We conducted a randomized phase II trial of cilengitide in pts with MM to evaluate the clinical efficacy at 2 different doses. Methods: Pts with stage IV or unresectable stage III non-choroidal melanoma who had no more than 1 prior systemic therapy were enrolled. Pts at least 18 years of age and with ECOG performance status of 0 to 2 were eligible. All pts underwent baseline tumor biopsy and were randomly assigned to either 500 mg or 2,000 mg intravenous (IV) EMD 121974 twice weekly, using the following stratification factors: 1) prior systemic treatment; 2) visceral metastases; 3) serum lactate dehydrogenase level; 4) tumor avβ3 overexpression, where overexpression is defined as > 25% of melanoma cells staining positive. The primary objective of this study was to determine the progression-free survival rate at 8 weeks. Results: Twenty-nine pts were enrolled, and 26 pts (14 at 500 mg; 12 at 2,000 mg dose) were treated. Patient characteristics for 500 mg and 2,000 mg arm, respectively, are as follows: median age, 57 and 61; percentage (% age) of male, 50% and 50%; % age of ECOG performance status of 0, 79% and 58%; % age of stage IV, 79% and 75%; % age of tumor avβ3 overexpression, 21% and 25%. Three of 26 pts were progression-free at 8 weeks (2 at 500 mg; 1 at 2,000 mg dose). One pt at 2,000 mg had a prolonged partial response after initial 28% enlargement of target lesions. There were no grade 3 or 4 adverse events (AEs) except one pt with grade 3 lymphopenia at 2,000 mg. Although both doses of EMD 121974 were well tolerated, the 2,000 mg was associated with higher incidences of grade 2 fatigue, arthralgia, lymphopenia, peripheral neuropathy, and GI AEs. Optional tumor biopsies were performed on day 8, and the correlative studies to examine the molecular changes in the tumor are currently in progress. Conclusions: IV EMD 121974, 500 or 2,000 mg twice weekly, was well tolerated but had minimal clinical efficacy as a single-agent for MM. Supported by NCI grant N01 CM-17003 and CA16672

No significant financial relationships to disclose.
Capecitabine (Cap) and oxaliplatin (Ox) in elderly and/or frail patients with metastatic colorectal cancer: The FOCUS2 trial
Authors: Seymour M. T. , Maughan T. S. , Wasan H. S. , Brewster A. E. , Shepherd S. F. , O'Mahoney M. S. , May B. R. , Thompson L. C. , Meade A. M. , Langley R. E.
Published: March 2020

9030

Background: Elderly/frail patients, though commonly treated, are under-represented in clinical trials. Evidence is needed to guide choices of drugs and doses in this population. Methods: FOCUS2 is a multicenter, 2x2 factorial randomized trial for patients with unpretreated metastatic colorectal cancer judged unfit for full-dose combination chemotherapy. After comprehensive health assessment (CHA), randomization was to: (A) simplified LV5FU2 infusional fluorouracil/leucovorin (FU); (B) OxFU; (C) Cap; or (D) OxCap. In each case, starting doses were 80% standard, with an option to escalate to full-dose at 6 weeks (wk). The factorial questions were: (A+B v C+D) - does replacing FU with Cap improve quality of life (QL)? (primary endpoint: improved global QL at 12 wk [QLQ-C30]); and (A+C v B+D) - how much does Ox improve efficacy in this population? (primary endpoint: progression-free survival (PFS). Results: 460 patients were randomized, 22% < 70 yrs; 35% 70–75 yrs; 43% > 75 yrs. 22% were performance status (PS) 0; 49% PS1; 29% PS2. Primary comparisons: (see table ): global QL did not favor Cap over FU. Comparison of PFS favored the addition of oxaliplatin but did not reach significance (HR 0.87, 95% CI 0.71–1.06, p=0.16). Secondary comparisons: Compared with FU, Cap did not affect RR, PFS or 60-day mortality, but it increased the risk of gr =3 toxicity. Oxaliplatin significantly improved RECIST response (RR) by wk 12, did not increase gr =3 toxicity or 60-day mortality, but reduced the chance of improved QL at 12 wk. Conclusion: In this frail elderly population, substituting Cap for FU did not improve overall QL or efficacy, and significantly increased toxicity. Addition of Ox gave significantly higher anticancer activity without increasing toxicity, but at the cost of some reduction in QL at 12 wk. Planned analyses include correlating baseline CHA with treatment outcome.

[Table: see text]

[Table: see text]
Osteopenia and osteoporosis in untreated non-Hodgkin's lymphoma patients: An important and potentially treatable survivorship issue in lymphoma
Authors: Thompson M. A. , Huen A. , Toth B. B. , Vassilopoulou-Sellin R. , Hoff A. O. , Murphy W. A. , Sanjoro H. , Bekele B. N. , Arbuckle R. B. , Hagemeister F. B.
Published: March 2020

9055

Background: Alkylating agents and steroids can cause premature osteoporosis, increasing the risk of vertebral and hip fracture. The bisphosphonate pamidronate every 3 months can reduce bone loss and the risk of new vertebral fractures in lymphoma patients receiving chemotherapy.(Kim et al., 2004 Am J Med) We are conducting a randomized study of the more potent bisphosphonate zoledronic acid in untreated non-Hodgkin's lymphoma (NHL) patients to study chemotherapy induced bone loss. Methods: During the accrual period, we report the baseline bone mineral density (BMD) characteristics for screened untreated NHL patients. Exclusion criteria included bone fractures, BMD T-scores worse than -2.0, CrCl < 60 mL/min, dental problems, prior bisphosphonate or significant steroid use. Patients accrued to the study were randomized to receive either: 1) oral calcium and vitamin D (Ca+D) or 2) Ca+D and 4 mg zoledronic acid IV at baseline and at 6 months. Results: Patient characteristics: 59 males and 55 females with median age 63 (range: 18–87). Lymphoma types: B-cell n=111, T-cell 3; follicular (FL) 56, diffuse large B-cell (DLBCL) 33, mantle cell 8, and others, totaling 114 patients. Of untreated NHL individuals screened for baseline BMD to date 11/114 (10%) had osteoporosis and 62/114 (54%) had osteopenia or osteoporosis. The lowest BMD was a T-score of -4.4. Other bone, dental, and endocrine abnormalities excluded some patients from treatment randomization. Patients with T scores < -2.0 were considered for off-study treatment with bisphosphonates. Osteopenia and osteoporosis were common across lymphoma subtypes: FL 25/56 (45%), DLBCL 20/33 (61%), mantle cell 6/8 (75%), and marginal zone 5/6 (83%). The low rate of osteopenia/osteoporosis of 25% for Burkitt/Burkitt-like lymphoma may reflect fast lymphoma kinetics without associated increase in bone loss. Conclusions: Baseline testing of BMD revealed osteopenia or osteoporosis in the majority of untreated NHL patients. This widely available and non-invasive test should be considered in untreated NHL patients. Our ongoing clinical trial will address the potential role of zoledronic acid in preserving bone density for survivors of NHL. ClinicalTrials.gov Identifier: NCT00352846

[Table: see text]
A randomized, double-blinded, pilot trial of aprepitant added to standard antiemetics during conditioning therapy for hematopoietic stem cell transplant (HSCT)
Authors: Bubalo J. S. , Leis J. F. , Curtin P. T. , Maziarz R. T. , Kovascovics T. J. , Meyers G. , McCune J. S. , Munar M. Y. , Hayes-Lattin B. , Jones N.
Published: March 2020

9112

Background: Antiemetic prophylaxis for standard dose chemotherapy has improved while that for high dose chemotherapy ± total body irradiation (TBI) has not. Aprepitant (A), a neurokinin-1 antagonist, was added to standard antiemetic therapy for planned conventional HSCT to test for improved emesis control. Methods: During cyclophosphamide (Cy)-based conditioning therapy patients were randomized to receive ondansetron (O) ± dexamethasone plus A or a placebo (P) on days of chemo/radiotherapy. The primary aim was to reduce N/V during and after HSCT conditioning. Nausea, emesis, and nutritional intake were evaluated from the onset of therapy through day +7. Busulfan doses were targeted to disease appropriate AUCs and pharmacokinetic (PK) analysis was performed on Cy, Cy- metabolites (HCY & CEPM), and A. Responses were defined as Complete (CR) - no emesis, mild-moderate nausea, and Major (MR) - 1–2 emesis on only 1 day with any level nausea or no emesis with severe nausea. Results: Fifteen patients have been randomized per arm. Eleven patients received TBI (1,200 cGy) CY (120 mg/kg) and 19 received Bu (16 mg/kg) CY (120 mg/kg). A/P was begun on Day -7 (125 mg) with the first O dose and given daily (80 mg) through day +4 (alone on days +1 through +4). Overall responses (CR + MR) were seen in 14/15 A patients and 7/15 P patients. (p=0.014) No emesis occurred in 10/15 A patients and 5/15 P patients (p=0.143). Preliminary PK show the observed AUCs of CY, HCY and CEPM, for both regimens and PK differences between the 2 regimens, were consistent with previously published data. Most busulfan patients, 87%, required dose adjustments (primarily reductions) to stay within target AUCs. Anti-seizure prophylaxis with phenytoin may significantly decrease A levels, but this didn't appear to be clinically relevant. Adverse effects were similar between arms. One case of sinusoidal obstruction syndrome occurred in the P arm. Conclusions: In this interim analysis, aprepitant added to standard antiemetics improved emesis prevention during Cy-containing conditioning therapy prior to HSCT, without significant changes in Cy pharmacokinetics or increased toxicity. Data on the target accrual of 40 patients will be presented.

[Table: see text]