Arnold J. Rotter

Phase II Study of Vorinostat for Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma

PURPOSE We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma. PATIENTS AND METHODS In this open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with ≤ 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability. RESULTS All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses [CR] and five partial responses [PR]). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue. CONCLUSION Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted.

Cystic pulmonary metastatic sarcoma

Neoplastic cavitary lesions are an unusual type of pulmonary metastases. The authors report two cases of cystic metastatic sarcoma of the lungs that illustrate the clinical, radiologic, and pathologic difficulties encountered in the diagnosis of these lesions. In one patient, multiple small, thin‐walled cystic metastases from a lower leg leiomyosarcoma were the only manifestation of metastatic disease. The cystic lesions did not change over an 8‐month period and a diagnosis of malignancy was not established until spontaneous pneumothorax, presumably due to rupture of the malignant blebs, prompted a thoracotomy. In the second patient, three thin‐walled bullae developed after treatment of noncystic pulmonary metastases from a lower‐leg synovial sarcoma. In both patients, the cystic lesions were not evident on chest radiographs, but were well visualized with computed tomography (CT), where they mimicked benign bullous disease. However, additional small cavitary lesions not seen with CT were present in resected pulmonary wedge specimens from both patients. A great degree of variability in the cellular composition of the cyst wall lining in both cases, and a lack of any solid neoplastic tissue masses in one case, led to histopathologic difficulties that required immunohistochemical studies for definitive diagnosis of the metastatic disease. These cases show that pulmonary bullae, even though thin‐walled and benign‐appearing on CT, may be a manifestation of pulmonary metastases. These lesions must therefore be surgically removed from patients in whom a curative resection of pulmonary metastases is warranted.

A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma.

This study examines the activity and tolerability of a regimen combining vorinostat and rituximab in patients with indolent B-cell non-Hodgkin lymphoma. A total of 28 patients with newly diagnosed or relapsed/refractory follicular, marginal zone, or mantle cell lymphoma, with 4 or less prior therapies were eligible for this open-label phase II study. Oral vorinostat 200 mg was administered twice daily on days 1–14 along with 375 mg/m2 of intravenous rituximab on day 1 of a 21-day cycle, continuing until disease progression or unacceptable toxicity. Primary end point was objective response rate, with secondary end points of progression-free survival, time to progression, duration of response, safety, and tolerability. Median follow up was 25.6 months and median number of vorinostat cycles was 11.5. Overall response rate was 46% for all patients, 67% for previously untreated, and 41% for relapsed/refractory patients. Median progression-free survival was 29.2 months for all patients, 18.8 months for previously treated patients, and not reached for untreated patients. The regimen was well tolerated over long treatment periods with the most common grade 3/4 adverse events being asymptomatic thrombosis, neutropenia, thrombocytopenia, lymphopenia, and fatigue. The vorinostat/rituximab combination exhibits activity in indolent B-cell non-Hodgkin lymphoma with an acceptable safety profile and durable responses. Re-treatment was effective in 2 of 3 relapsing responders. This phase II clinical trial was registered at clinicaltrials.gov identifier: 00720876.

Lung cancer screening, version 3.2018

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.

Valproic acid monotherapy leads to CR in a patient with refractory diffuse large B cell lymphoma

The rapidly growing understanding of the mechanism underlying transcriptional regulation at the histone level, has already led to FDA approval for three drugs in this class. Azacytidine and deoxycytidine, believed to operate as methyltransferase inhibitors, have been FDA approved for use in myelodysplastic syndrome, with activity also shown in acute leukemias [1]. The third drug, vorinostat (SAHA, Zolinza), a histone deacetylase inhibitor (HDACi), has been FDA approved for use in CTCL, the first approved indication for a drug designed as a histone deacetylase inhibitor [2]. Several other HDACi are in trials for CTCL, which seems to respond quite dramatically to this class of agents both in vivo and in vitro [3]. Preclinical data suggests that HDACi may be effective against many lymphoma types other than CTCL. HDACi treatment leads to decreased levels of bcl-2 in mantle cell lines [4] and leads to accumulation of acetylated BCL-6, which causes cell cycle arrest and apoptosis in B cell lymphoma lines [5]. In the broader picture, HDACi treatment has shown effect upon expression of many targets which could have an impact upon lymphoma survival, including numerous DNA damage response and proapoptotic proteins [6]. There are several classes of HDACi, including cyclic peptides, hydroxamic acids, benzamides, and short chain fatty acids. Among the latter, is valproic acid, which has been used for many years to treat seizure disorders, but was recently demonstrated to have histone deacetylase inhibitor activity [7]. The addition of valproic acid to hypomethylating agents has shown beneficial activity in myelodysplastic syndrome and AML [8], but has not been studied clinically in B cell lymphoma. We present a dramatic response in a patient with refractory diffuse large B cell lymphoma to valproic acid as monotherapy. MB is a 64-year-old woman with a history of recurrent diffuse large B cell lymphoma who has been followed at City of Hope since January of 2005. She was diagnosed with stage I left sided breast cancer in 1995 and underwent lumpectomy, lymph node dissection, and local radiation; remission was achieved and there has been no evidence of recurrence. In early 2002, she complained of progressive lower back pain radiating down her left leg; an MRI of the lumbosacral spine in June 2003 revealed a large retroperitoneal mass measuring 86 46 5 cm along with abnormal signal in several vertebrae. CT guided biopsy confirmed a diagnosis of diffuse large B-cell lymphoma. Immunophenotyping was consistent with a follicular center cell origin, bcl-2þ, bcl-6þ; blocks were recently reanalyzed and now classified as being of germinal center origin, staining CD10þ, bcl-6þ, and MUM-17[9]. Staging was consistent with stage IV disease with several bony areas of involvement in the spine and ribs. Bone marrow was involved with B cell lymphoma with a mixture of small and large cells and significant fibrosis. She had normal blood counts and LDH and no B symptoms. She received six cycles of CHOP and rituximab with repeat staging, which showed that her retroperitoneal mass had decreased

Age-Related Changes in Nanoparticle Albumin-Bound Paclitaxel Pharmacokinetics and Pharmacodynamics: Influence of Chronological Versus Functional Age

PURPOSE This study evaluated age-related changes in pharmacokinetic and pharmacodynamic parameters of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in patients with metastatic breast cancer. METHODS Forty patients received nab-paclitaxel (100 mg/m(2) weekly for 3 weeks followed by a 1-week break) as first- or second-line chemotherapy. Blood samples were collected for analysis, and response was assessed every two cycles. Planned statistical analyses included linear regression to examine the relationship between age and pharmacokinetic variables (ln clearance [CL] and ln area under the curve [AUC]) and two-sided two-sample t tests to evaluate age differences in pharmacodynamic variables. The association between chemotherapy toxicity risk scores and pharmacokinetic and pharmacodynamic variables including grade ≥ 3 toxicity were examined post hoc. RESULTS Of 40 patients enrolled, 39 (98%) were evaluable (mean age: 60 years; range: 30-81 years). A partial response was achieved in 31%, and 38% had stable disease. There was a borderline positive association between age and 24-hour ln AUC (slope = 0.011; SE = 0.006; p = .055). Grade 3 toxicity was experienced by 26% (8% hematologic, 18% nonhematologic). There were no differences in age based on the presence of grade 3 toxicity (p = .75), dose reductions (p = .38), or dose omissions (p = .15). A significant association was noted between chemotherapy toxicity risk score category and presence of grade 3 toxicity (toxicity rate by risk score category: low, 5 of 30 patients; medium, 3 of 6 patients; high, 2 of 3 patients; p = .041). CONCLUSION A borderline significant relationship exists between age and 24-hour AUC, but no differences were noted for pharmacodynamic variables (grade 3 toxicity, dose reductions, or dose omissions) based on age. There is an association between toxicity risk score and grade ≥ 3 chemotherapy toxicity and pharmacokinetic variables. The treatment is well tolerated across all age groups.

A Phase II Trial of Older Adults with Metastatic Breast Cancer Receiving nab-Paclitaxel: Melding the Fields of Geriatrics and Oncology

Micro‐Abstract nab‐Paclitaxel may be an attractive therapy for older adults because of its efficacy, the infrequency of allergic reactions, and the lack of need for steroid pre‐medications. We evaluated the tolerability and efficacy of nab‐paclitaxel in older adults with metastatic breast cancer, as well as the relationship between a geriatric assessment‐based toxicity risk score and chemotherapy toxicity, dose reductions, dose delays, and hospitalizations. Patients with intermediate/high toxicity risk scores had higher risk of grade ≥ 3 toxicity than those with low risk scores, and a higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. A geriatric assessment‐based risk score can help weigh the risks and benefits of chemotherapy in older adults, and should be incorporated into future trials testing new therapies in this population. Introduction: Phase II clinical trials including geriatric assessment (GA) measures are critical for improving the evidence base for older adults with cancer. We assessed the efficacy and tolerability of nab‐paclitaxel in older adults with metastatic breast cancer (MBC). Patients and Methods: Patients aged ≥ 65 years with MBC and ≤ 1 previous line of chemotherapy received 100 mg of nab‐paclitaxel on days 1, 8, and 15 of a 28‐day cycle. A GA was completed pre‐chemotherapy, and the validated Cancer and Aging Research Group (CARG) chemotherapy toxicity risk score was calculated. Relationships between tolerability (number of courses, hospitalizations, dose reductions, and toxicity) and risk score were assessed using general linear models, Student t tests, and the Fisher test. Response rate and progression‐free survival were evaluated using the Kaplan‐Meier method. Results: Forty patients (mean age, 73 years; range, 65‐87 years) were included. The median number of cycles was 6, 75% (n = 30) of patients had ≥ 1 dose hold, and 50% (n = 20) had ≥ 1 dose reduction. Fifty‐eight percent (n = 23) had treatment‐related ≥ grade 3 toxicities, and 30% (n = 12) were hospitalized owing to toxicity. Thirty‐five percent (n = 14) responded, and the median progression‐free survival was 6.5 months (95% confidence interval, 5.5 months to undefined). Patients with intermediate/high toxicity risk scores had higher risk of grade ≥ 3 toxicity than those with low risk scores (odds ratio, 5.8; 95% confidence interval, 1.3‐33.1; P = .01). A higher mean risk score was associated with higher likelihood of dose reductions and hospitalizations. Conclusions: Among older adults with MBC receiving weekly nab‐paclitaxel, more than one‐half experienced ≥ grade 3 chemotherapy toxicity. However, a GA‐based risk score could predict treatment tolerability.

P5-19-05: Age-Related Changes in the Pharmacokinetics (pK), Response, and Toxicity of Weekly nab-Paclitaxel in Patients with Metastatic Breast Cancer (MBC).

Background: Although cancer is a disease of aging, few studies have evaluated the association between patient age and the pK or pharmacodynamics (pD) of cancer therapeutics. The goals of this study were 1) to evaluate the age-related changes in the pK and pD of weekly nab -paclitaxel in patients with MBC; 2) to determine response rate; and 3) to explore the relationship of age with pK and pD parameters (i.e., dose reductions, dose delays and grade ≥ 3 toxicities). Patients and Methods: Forty patients with MBC, receiving 1 st or 2 nd line chemotherapy, entered an IRB approved protocol to evaluate the age-related changes in the pK of weekly nab -paclitaxel administered at 100 mg/m 2 IV for 3 weeks followed by a 1-week break. Patients were accrued from 4 age strata 70 years of age. Blood samples were collected for pK analysis with the first dose of nab -paclitaxel. Response was assessed every 2 cycles. Toxicity was graded using the NCI Common Toxicity Criteria for Adverse Events (v 3.0) and was adjudicated as attributable to nab -paclitaxel if it was possibly, probably, or definitely related. Linear regression analysis was used to examine the strength of the relationship between patient age and natural logarithm of 24 hour area under the curve (AUC). Two-sided two-sample t-tests were used to assess if there was a difference in mean age based on the presence of pD variables (i.e., dose reductions, dose delays and grade ≥ 3 toxicities). The significance level was set to 0.05. Results: Of the 40 patients who entered the study, 39 (98%) were evaluable with a mean age of 60 (SD=13.4; min=30; max=81). Patients were accrued in the following age cohorts: 70 (n= 9; 23%) years of age. The median number of courses completed was 4 (min=1, max=21). The response rate was: 0% (n=0) CR, 31% (n=12) PR, 38% (n=15) SD. Grade 3 toxicity was experienced by 26% (n=10). We observed 8% (n=3) grade 3 hematological toxicities [neutrophils (n=1; 3%), leukocytes (n=2; 5%)] and 18% (n=7) grade 3 non-hematological toxicities [nausea and hypophosphatemia (n=1; 3%), diarrhea and infection without neutropenia (n=1; 3%), fatigue (n=2; 5%), hyponatremia (n=1; 3%), and infections without neutropenia (n=2; 5%)]. There were no cases of grade 4 or 5 toxicity. Grade 2 sensory neuropathy was experienced by 8% (n=3; no cases in the 70+ age cohort). Dose reductions or course delays were experienced by 62% (n=24) and 21% (n=8), respectively. There was a borderline significant positive association between age and natural logarithm of total nab -paclitaxel 24 hour AUC (coef=.01; se=.006; p=0.055; n=36). There were no differences in the mean ages based on the presence of grade 3 or higher toxicity (p =0.75), need for dose reductions (p=0.48), or need for dose delays (p=0.61). Discussion: There is a borderline statistically significant relationship between age and 24 hour AUC but no differences in mean age based on pD variables (i.e., dose reductions, dose delays and grade ≥ 3 toxicities) were identified. The treatment is well-tolerated across all age groups. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-05.