Kathy Tolzien

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).

Lenalidomide Monotherapy in Chemotherapy-Naive, Castration-Resistant Prostate Cancer Patients: Final Results of a Phase II Study

BACKGROUND We investigated the activity of lenalidomide, which has antiangiogenic, antineoplastic, and immunomodulatory properties, in chemotherapy-naive, castration-resistant prostate cancer (CRPC) patients. PATIENTS Patients received 25 mg/d lenalidomide for 21 days in 28-day cycles, until disease progression or unacceptable toxicity developed. Endpoints included overall response rate and clinical benefit (overall response + stable disease), toxicity, time to radiographic progression, and time to prostate-specific antigen (PSA) progression, overall survival, and quality of life. RESULTS Thirty-two patients were enrolled in the study; of these, 77% (n = 25) had Gleason scores ≥ 7. The median age was 74 years (58-89 y), the median PSA level was 66 ng/mL (2-919 ng/mL), and 5 of 32 patients (17%) had liver or lung involvement. The median number of lenalidomide cycles was 3 (1-16 cycles). Stable disease was seen in 20 patients, for a clinical benefit rate of 63%. The median time to radiographic progression was 4 months (2-16 mo); the median overall survival was 20 months. Of 27 PSA-evaluable patients, 13 (48%) had a decline in PSA level; 3 (11%) had > 50% PSA decrease; the median time to PSA progression was 3 months (2-9 mo). Grade 3/4 hematologic toxicities were the most common adverse events without adverse impact on quality of life. Serious adverse events occurred in 14 patients (44%), including 1 patient (3%) with a rash definitely related to lenalidomide. CONCLUSION Lenalidomide monotherapy demonstrates modest activity in chemotherapy-naive CRPC.

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.

Bortezomib (Velcade), Rituximab, Cyclophosphamide, and Dexamethasone Combination Regimen Is Active as Front-Line Therapy of Low-Grade Non-Hodgkin Lymphoma

OBJECTIVE To evaluate the efficacy and toxicity of the combination of VRCD (velcade/rituximab/cyclophosphamide/dexamethasone) in chemotherapy-naïve low-grade non-Hodgkin lymphoma or patients with transplantation-ineligible mantle cells. METHODS The patients were treated with velcade, at 1.6 mg/m(2), on days 1, 8, 15, and 22 on every 35-day cycle. Rituximab was given at 375 mg/m(2) on the same days as velcade during cycle 1 and then only on day 1 in subsequent cycles. Dexamethasone was given orally at 40 mg on days 1, 2, 8, 9, 15, 16, 22, and 23. Cyclophosphamide was administered orally at 400 mg/m(2) on days 1-4. The patients had to meet criteria to initiate therapy and had to demonstrate adequate performance status and organ function. RESULTS Twelve patients were enrolled, after which the study was closed due to a lack of funding. The median age was 68 years (37-83 years), with 83% having stage III/IV disease. Five patients had marginal zone, 4 had follicular, 2 had small lymphocytic, and 1 had mantle cell histologies. The overall response rate was 90% (complete response, 54%). At a median follow-up of 22 months, 9 (75%) patients remain alive, and the median time to progression has not been reached. A third of the patients required dose reductions after a median of 6.5 cycles. No grade 3 or 4 peripheral neuropathy was witnessed. CONCLUSIONS Although the number of studied patients is small, VRCD appears safe and active as front-line therapy for low-grade non-Hodgkin lymphoma. Further studies are justified.

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.

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.

Effect of lenalidomide (LEN) on biochemical responses and clinical benefit (CB) as a single agent in chemotherapy-naive castration-resistant prostate cancer (CRPC).

128 Background: LEN has anti-angiogenesis and immunomodulatory properties making it ideal to investigate in CRPC. We report on a phase II study investigating LEN in chemotherapy-naïve CRPC patients (pts) Methods: Eligible pts received LEN at 25 mg daily on days 1 - 21 every 28-days until progression. Daily aspirin or coumadin were required. Responses were assessed every 2 cycles. Toxicity was assessed every cycle. Primary end point: The CB of LEN [Sum of complete response (CR), partial response (PR) and stable disease (SD)]. Secondary end points: Toxicity, time to radiographic and PSA progression (TTP and TTP-PSA), time to next treatment (TTNT), overall survival (OS), and LENs impact on quality of life (QOL). RESULTS 31 pts were enrolled; 27 response-evaluable (1 withdrew consent, 3 off per choice after adverse events). Median age is 74 (range 58-89) with 24 (77%) having Gleason ≥ 7 disease. Median PSA is 66 (2.1-918.6). Six pts (19%) had liver/lung involvement. Fourteen pts (51%) showed biochemical response with 4 (15%) having >50% PSA drop. TTP-PSA is 4 months (2-11). No radiographic responses seen but 17 pts had SD for a median of 4 months (2-16) (CB=55%). Median number of LEN cycles was 3 (2-15). With a median follow-up of 18 months (5-38), 17 patients (55%) remain alive; median OS of 18 months. Grade 3/4 hematologic toxicities were most common (neutropenia 41%, leukopenia 12%, anemia 9%, thrombocytopenia 9%). Other grade 3/4 toxicities: venothromboembolism, atrial fibrillation, and dehydration (6% each). Serious adverse events (SAEs) were witnessed in 10 pts (32%) with only 1 (3%, rash) definitely related to LEN. Others were not related or possibly related. Of 27 pts, 7 (26%) had a dose reduction and 2 (7%) required two dose reductions. Dose reductions occurred after cycle 3. QOL scales suggested no adverse impact. Median TTNT is 2 months (9 pts received chemotherapy, 10 pts went onto studies, 3 pts received hormonal therapies, 4 pts received radiation, 3 pts had no therapy yet, and 2 pts remain on LEN). CONCLUSIONS LEN is active as monotherapy in CRPC. Biochemical responses are witnessed and clinical benefit is observed. Myelosuppression is the most common toxicity.

Phase I study of imatinib mesylate (IM) and sorafenib (S) in patients (pts) with refractory castration-resistant prostate cancer (CRPC).

146 Background: IM is an inhibitor of protein-tyrosine kinases including those that are over-expressed in bone metastases and primary prostatic adenocarcinoma. S is a potent inhibitor of wild-type and mutant BRAF, C-RAF, VEGFR2, VEGFR3, FLT3, and PDGFR-beta with modest activity in CRPC. We combined IM+S to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) in CRPC pts. METHODS CRPC pts with measurable disease and adequate organ function who failed chemotherapy were eligible. Dose escalation followed a 3+3 study design. Toxicity was scored following CTCAEv3. Responses were defined by RECIST1.0. IM pharmacokinetics (PK) were determined on day 15, 4 h post-dose with a validated LC-MS assay. RESULTS Seventeen pts were enrolled; 10 were evaluable. At dose level 0 (DL0), 6 pts received S at 400 mg S with 300 mg of IM both given daily. At DL1, 4 pts received 400 mg S twice/day with 300 mg IM daily; inevaluable pts received <1 cycle (5 withdrew consent, 1 rapid early progression, 1 non-compliant). Median age was 73 (57-89) and median PSA was 284 ng/ml (11.7-9027). Median number of prior non-hormonal therapies was 3 (1-12) and 12 pts had Gleason score ≥7 while 15 pts had bone as the major site of metastases. On DL0, 1/6 pts had DLT (gr 3 hand/foot). On DL1, 2/4 pts had DLT (1 gr 3 hand/foot, 1 gr 3 diarrhea). MTD was 300 mg IM and 400 mg S both qd. No biochemical responses were observed. Two pts on DL1 had stable disease radiographically by RECIST (overall clinical benefit for the entire cohort 20%). Median time to progression was 2 months (1-5) while median OS was 6 months (1-30+) with 3/17 patients (17%) remaining alive at a median follow-up of 21 months. Of patients enrolled, 10 had PK data, which suggested that S reduced IM clearance by 40%, resulting in 60% increased exposure (P = 0.009; two-tailed t-test on log-transformed values, compared to historic data). CONCLUSIONS To our knowledge, this is the first report to show that IM+S can be safely combined in CRPC. The phase II recommended dose for future trials is 300 mg IM and 400 mg S, both given daily. The PK interaction might be of questionable clinical relevance because IM concentrations are within the commonly observed range.

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.

A phase II pilot trial investigating the efficacy and activity of single agent granulocyte macrophage colony-stimulating factor as maintenance approach in castration - resistant prostate cancer patients responding to chemotherapy.

Purpose: To investigate the toxicity and efficacy of GM-CSF in castration-resistant prostate cancer (CRPC) patients who maximized their response to systemic chemotherapy. Materials and Methods: CRPC patients who maximized their response to either docetaxel or mitoxantrone chemotherapy were eligible if they demonstrated adequate performance status, liver, kidney, and bone marrow function. Maximum response to chemotherapy was defined as either receiving at least 8 cycles of chemotherapy without radiographic or biochemical progression, receiving less than 8 cycles as long as the prostate-specific antigen (PSA) changes by less than 10%, or being off chemotherapy for less than 12 weeks without disease progression. Patients received GM-CSF at 250 mcg/m2 subcutaneously for 14 days followed by 14 days of rest. GM-CSF was continued until disease progression. Results: Fifteen patients were enrolled of which all were evaluable for toxicity and 13 were evaluable for efficacy. Median age was 78 (range 66-96) and 93% of patients had a Gleason score ≥ 7. Biochemically, 2 patients (15.3%) attained partial response (PR) and 4 (30.7%) had stable disease (SD). Median time to PSA progression was 6 months (range 4-12). Radiographically, 9 patients (69.2%) had SD that lasted a median of 6 months (range 2-10). With a median follow-up of 24 months from starting GM-CSF (range 2-38), 2 patients (13.3%) remain alive and well. Median OS from start of any chemotherapy was 21 months (range 10-44). GM-CSF was well-tolerated with minimal expected manageable toxicities. Conclusions: GM-CSF is active post-chemotherapy in CRPC patients. Further studies with GM-CSF in this setting are warranted.