Angel Galvez

Erlotinib Has Moderate Single-agent Activity in Chemotherapy-naïve Castration-resistant Prostate Cancer: Final Results of a Phase II Trial

OBJECTIVES To investigate the efficacy and toxicity of single-agent erlotinib in chemotherapy-naive castration-resistant prostate cancer. METHODS Eligible patients received erlotinib at 150 mg daily until disease progression. Toxicity was assessed every 2 weeks and responses every 8 weeks. Primary end point was assessing the overall clinical benefit measured as the sum of stable disease, partial response, and complete response. Secondary end points included time to disease progression, overall survival, and toxicity using the National Cancer Institute Common Toxicity Criteria version 3.0. RESULTS A total of 29 patients were enrolled in this study. Median age was 77 and median prostate-specific antigen was 66.3 ng/mL. Of 22 evaluable patients, 2 met the criteria for partial response and 5 demonstrated stable disease for an overall clinical benefit of 31%. PSA-doubling time improved in all responding patients to a median of 6 months from 3 months before entry into the study. One patient remained in study at 28 months, and 2 had > 50% decrease in their serum PSA level. Median time to disease progression was 2 months, but at 12 months, 9% of patients were progression-free. Median overall survival was 16.3 months, with 1- and 2-year survival rates of 58% and 27%, respectively. Erlotinib was well tolerated, with only 2 patients requiring dose reductions. Adverse events were as expected with grade 3 or 4 diarrhea, fatigue, and rash occurring in 10%, 6%, and 6% of patients, respectively. CONCLUSIONS Erlotinib has moderate activity in chemotherapy-naive castration-resistant prostate cancer, with some patients showing biochemical response. Future studies investigating this agent in combination are warranted. (This trial was registered at http://NCI.gov, NCT00272038).

Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII

Eight patients with inhibitors to factor VIII (4 hemophilia A and 4 nonhemophilic) were treated with recombinant activated factor VII (rFVIIa) to control severe abdominal bleeding. The recombinant factor was supplied under an open‐label, emergency‐use program to patients previously unresponsive to one or more alternative therapies. Therapy with rFVIIa was administered for nine separate bleeding events; one patient was treated for two separate bleeding episodes. Patients were treated for an average of 9 days and received a mean total dose of 5.2 mg of rFVIIa for control of bleeding. Treatment was considered successful and hemostasis adequate in 7 of the 9 episodes (78%). Treatment with rFVIIa was partially successful in one other episode. Four patients in this series experienced serious adverse events; all the adverse events were considered unrelated to rFVIIa therapy. The results of this limited series indicate that rFVIIa is an effective means of managing life‐threatening abdominal bleeding in individuals with hemophilia or acquired antibodies to factor VIII. Am. J. Hematol. 63:109–113, 2000.

Efficacy and safety of clofarabine in relapsed and/or refractory non-Hodgkin lymphoma, including rituximab-refractory patients.

Currently, no standard therapy exists for patients with relapsed and/or refractory non‐Hodgkin lymphoma (NHL) who are ineligible for transplantation or who have failed after bone marrow transplantation. The authors of this report investigated the safety and efficacy of clofarabine (CLO) in these patients.

Role of Sorafenib in Overcoming Resistance of Chemotherapy-Failure Castration-Resistant Prostate Cancer

BACKGROUND Sorafenib promotes apoptosis through downstream pathways that can be deregulated in CRPC. We hypothesized that sorafenib could overcome chemotherapy resistance in CRPC. PATIENTS AND METHODS Eligible patients were those whose disease had progressed during chemotherapy (docetaxel or mitoxantrone) or within 12 weeks of stopping either. Patients then continued or resumed their last chemotherapy regimen with the addition of sorafenib 400 mg twice daily. Patients received a maximum of 6 cycles of chemotherapy/sorafenib followed by sorafenib alone until disease progression. The primary end point was combination safety. Secondary end points were overall response, percentage of SD, and time to progression (TTP). RESULTS Twenty-two patients (21 evaluable) were enrolled (16 patients with Gleason score ≥ 7). Median age was 68 years (range, 59-83 years). Median prostate-specific antigen (PSA) was 142 ng/dL (range, 13.6-9584). Visceral and bone disease were present combined in 9 patients (41%). Ten patients (47.6%) showed biochemical response (19% with > 50% PSA decline) and 16 patients (76%) achieved radiographic stability (according to Response Evaluation Criteria for Solid Tumors) after starting sorafenib for a median duration of 6 months (range, 4-12 months). Grade 3/4 nonhematologic toxicities were fatigue (n = 7, 32%), palmar-plantar erythrodysesthesia (n = 4, 18%). Dose reduction of sorafenib occurred at least once in 15 patients (68%) because of palmar-plantar erythrodysesthesia (22%) and fatigue (22%). With a median follow-up of 19 months (range, 3-46 months), median overall survival was 8 months. TTP according to PSA level was 3 months and TTP according to imaging studies and/or clinically was 6 months. Median number of treatment cycles given was 6 (range, 1-10). CONCLUSION Sorafenib can be combined safely with chemotherapy and in some patients overcomes chemotherapy resistance.

Are Tri‐Ethnic Low‐Income Women with Breast Cancer Effective Teachers of the Importance of Breast Cancer Screening to Their First‐Degree Relatives? Results from a Randomized Clinical Trial

Abstract:  The purpose of this study was to determine the efficacy of women with breast cancer as teachers of the importance of breast cancer screening to their first‐degree female relatives. The sample was restricted to low‐income working age women recruited from four hospitals. The study design was a randomized clinical trial. At each hospital, breast cancer patients (probands) were randomized into one of two study groups: (i) intensive, individual educational training on breast cancer screening or (ii) standard clinic education on breast cancer screening. The probands were instructed to teach at least one of their first‐degree female relatives (21+ years of age) about breast cancer screening techniques. Three to six months after the enrollment of the probands, their relatives were contacted by telephone to determine breast cancer screening practices. A total of 79 probands and 96 relatives participated in the study. Relatives in the education group when compared with the control group were: 1.25 times more likely to have clinical breast examination (p = 0.005), 2.83 times more likely to have scheduled a clinical breast examination (p = 0.046), and, 1.36 times more likely to have been told about performing breast self‐examination (p = 0.05). Additionally, relatives in the education group were more likely to have received a pamphlet on breast cancer screening (RR = 1.58, p = 0.009) and have discussed the importance of breast cancer screening (RR = 1.33, p = 0.020) from the proband. Special education training did not impact mammography utilization of the relatives. From these findings, a tri‐ethnic group of low‐income women with breast cancer can be effective teachers of breast cancer screening practices, at least for promoting clinical breast examination and transmitting messaging for performance of breast self‐examination if given the adequate training.

A phase II study evaluating the toxicity and efficacy of single-agent temsorilmus (TEM) in chemotherapy-naive castration-resistant prostate cancer (CRPC): First report of suggested activity.

165 Background: PTEN tumor suppressor gene is mutated in CRPC allowing for downstream protein activation including mammalian target of rapamycin (m TOR) leading to tumor cell growth and survival. We investigated TEM; an mTOR inhibitor, in chemotherapy-naïve CRPC patients (pts). METHODS Eligible pts received TEM at 25 mg weekly until disease progression. Responses were assessed every 8 weeks and toxicity every 4 weeks using CTCAE v.3. Quality of life (QOL) data were collected every cycle using two previously validated scales. Primary end point: Clinical Benefit (CB) [sum of complete response (CR), partial response (PR), and stable disease (SD)]. Secondary end points: Toxicity, time to next treatment (TTNT), time to radiographic and PSA progression (TTP and TTP-PSA respectively), impact on QOL, and overall survival (OS) Results: To date, 18 pts have been enrolled. Median age was 75 (57-89) with Gleason ≥7 in 14 (77%), and median PSA 211.3 (10.8-1,449). Ten pts (55.5%) had bone and visceral disease. Median time on androgen deprivation therapy (ADT) was 60 months (17-240). Previous therapy included: surgery 3, brachytherapy 3, external radiation 5, ADT 7. All pts were evaluable for toxicity and 16 for response. Six pts (33%) were taken off study without progression (2 withdrew, 3 persitsant thrombocytopenia, 1 non-compliance). Biochemical response data was available for 15 pts (2 not evaluable, 1 refused), of which 4 (26%) had PSA decline and 1 (6%) had >50% drop in PSA. TTP-PSA was 2 months (2-12). Sixteen pts were evaluable by RECIST; 2 PR and 9 SD for a CB of 69% (11 of 16). TTP or event (toxicity that took pts off study was an event) was 3 months (3-10) and TTNT was 4 months (2-11). With a median follow up of 18 months, 8 pts (44%) remain alive for a median OS of 13 months. Most commonly reported grade 3/4 toxicities: Thrombocytopenia (22%), hyperglycemia, hypophosphatemia, and fatigue (17% each), pneumonia and anemia (12% each). TEM did not impact QOL adversely without treatment-related mortality. CONCLUSIONS TEM has activity in CRPC; some pts have CB without adverse impact on QOL. TEM should be further investigated in combination therapy in CRPC.

Overcoming chemotherapy resistance in patients (pts) with chemotherapy-failure, castration-resistant prostate cancer (CRPC) with sorafenib.

127 Background: SOR is an oral multi kinase inhibitor that promotes apoptosis through downstream pathways that can be deregulated in CRPC leading to chemotherapy resistance. We hypothesized that SOR Could overcome chemotherapy resistance in non-responders or in those who progress shortly after stopping chemotherapy. METHODS Eligible pts were those who progressed while receiving chemotherapy [docetaxel (D) or mitoxantrone (M)] or within 12 weeks from stopping it. Pts were then continued or resumed on their last chemotherapy with the addition of SOR at 400 mg PO BID. Pts were allowed a maximum of 6 cycles of chemotherapy +SOR followed by SOR as monotherapy until progression. Primary end point: Safety of SOR+ chemotherapy. Secondary end points: Toxicity, time to progression (TTP). And responses (biochemical and radiographic) Results: Twenty-two pts were enrolled; 21 evaluable (73% Gleason ≥ 7). Median age was 68 (59-83). Median PSA was 142 ng/dl (13.6-9,584). Median time from last chemotherapy to SOR was 4 weeks. Visceral and bone disease was present in 64%. D was given in 16 pts while M in 6. Ten pts (45%) showed biochemical response (18% with >50% PSA decline). Despite progression before being on study, 16 pts (76%) achieved SD after starting SOR for a median duration of 6 months (4-12). The combination of SOR with either chemotherapy agent proved safe. Main grade 3/4 non-hematologic toxicities: Fatigue 7 (32%), 4 (18%) hand/foot syndrome, hypocalcemia and hyperglycemia in 2 pts (9%) each. Grade 3/4 leukopenia was seen in 7 (31%), neutropenia in 6 (27%), and thrombocytopenia in 2 (9%). Dose reduction of SOR occurred at least once in 15 pts (68%). Major reasons are hand/foot syndrome (22%), fatigue (22%), rash (13%), and neutropenia (9%). With a median follow-up of 19 months (3-46), 5 pts (23%) remain alive for a median OS of 8 months. TTP by PSA was 3 months (2-6) and TTP by imaging and/or clinically was 6 months (2-12). Median number of treatment cycles given was 6 (1-10). CONCLUSIONS SOR can safely be combined with chemotherapy. SOR overcomes chemotherapy-resistance and shows biochemical and radiographic stability in this refractory pt population.