Pts In Partial Response Research Articles

Dacarbazine (DTIC) plus bevacizumab (B) combination therapy in chemotherapy (CTh)-naïve advanced melanoma (MM) patients (pts): A phase II study.

8536 Background: Advanced MM pts' poor prognosis is not improved by the neither of the 2 FDA approved agents, DTIC and IL-2 (median survival-time < 9 month [mo]; 5-yr survival-rate < 5%). Single-agent DTIC has average response-rate of 10% and median response-duration of 5-6 mo, being poly-CTh never proven to be superior. To improve such sober results, different DTIC- combinations have been proposed. MM in vitro models showed VEGF transcription up-regulation by DTIC, suggesting DTIC/anti-VEGF combination as an intriguing exploiting path. Methods: Between July 2006-September 2009, at IEO, Milan, 40 CTh-naïve advanced MM pts underwent CTh with DTIC (800 mg/mq q4w) + B (10 mg/kg q2w), being disease evaluated at each access by physical examination and every 3 cycles by whole-body (wb) CT-scan, according to RECIST criteria. Response rate, median TTP and safety were analyzed. Results: 36/40 pts were evaluated at the analysis-time, with 4 screening failures (3 pts: brain metastasis detection at the pre-study wb CT-scan; 1pts: bleeding risk). Male/Female = 23/13; median age was 57 yr. PS 0/1 = 32/4. 6 pts (16.6%) developed partial response (PR), 13 (36.1%) stable disease (SD ≥ 24w = 10 pts, 25.6%); 17 (47.2%) progressive disease (PD; 8 pts: RECIST-criteria PD at the first CT-scan evaluation; 9 pts: early clinical PD). PR pts were on average older (65.7 yrs; range 46.3-74.1) than both SD (57.2 yrs; range 33.1-78.5) and PD pts (51.4 yrs; range 31.6-76.3). Median TTP was 6 mo (95% CI 2.8-12.6). Furthermore, exploratory data analysis interestingly shows 42.2% clinical benefit (defined as PR+SD ≥ 24w) and 16.5 mo (95% CI 5-31.5) median survival. Treatment was well tolerated (mild hypertension and mucositis [8/36], easily controlled by symptomatics); 3 SAEs were recorded: 2 major cardiac events and 1 allergic reaction to B at the first administration. Conclusions: Long-lasting response obtained in both SD and PR pts and mild side effects support DTIC/B as a promising combination in advanced MM pts. We are currently investigating whether the molecular pattern and gene profiling of each patient can predict responders vs. nonresponders to the DTIC/B combination. No significant financial relationships to disclose.

Post Tandem Autologous Stem Cell Transplant Maintenance Therapy with Bortezomib Improves Remission Duration and Quality of Response in Multiple Myeloma Patients.

Abstract 4939 BackgroundSingle or tandem Autologous Stem Cell Transplantation (ASCT) has been considered standard approach in adult (<65y) Multiple Myeloma (MM) patients (pts), however post ASCT disease progression occurs in the majority of cases suggesting that post ASCT maintenance treatment might be useful. The role of Bortezomib in the post-ASCT context is still not well defined. In December 2007 this single center study was activated in the aims to assess the impact of Bortezomib maintenance a) on time to progression (TTP), b) the possible toxicity related to a prolonged administration of the agent. Patients and MethodsBetween October 2002 and July 2008, at Hematology Unit of S. Giovanni Hospital, 24 pts (median age 59.5y, min 38-max 67y) with newly diagnosed intermediate/advanced MM underwent single (8), or tandem (16) ASCT, respectively. Of these, 13 pts autotransplanted (8 single and 5 tandem) between 2002 and 2007, who did not receive any treatment post-ASCT, were considered as historic control group, while the remaining 11 autotransplanted from December 2007 to September 2008, received Bortezomib as maintenance treatment. Maintenance schedule consisted of Bortezomib as single agent given at dosage 1.5 mg (total dose) every 15 days until progression. Response was evaluated according to the International Myeloma Working Group uniform response criteria, while minimal residual disease (MRD) was assessed every 3 months on bone marrow (BM) samples by 6-colour BDFACS CANTO II. Abnormal plasma cells (APC) were identified using an Ab panel against the following markers: CD38, CD138, CD19, CD20, CD45, CD56, CD117, CD28, CD200. The condition was optimized in order to obtain a sensitivity level ' 1×10-3 (<0.01). Moreover, the presence of peripheral neuropathy (PN) was monitored before maintenance start, then every 3 mo by neurophysiologic tests including motor and sensory conducting studies. ResultsIn the Bortezomib group, post -2nd ASCT, 5 pts achieved complete (CR) or a very good partial response (VGPR), 4 partial response (PR), and 2 maintained stable disease (SD), respectively; the overall response rate was 82%, with 45% CR+VGPR. Maintenance was started in a median time of 3.8 mo (min 1.7 - max 13.7 mo). As of July 2009, after a median maintenance length of 16.2 mo (min 4.1 - max 19 mo), all 11 pts are alive. As disease status, of the 4 pts in PR after 2nd ASCT, 1 achieved stringent CR (sCR), 1 CR and 2 progressed, respectively. The 5 pts who were previously in CR/VGPR maintained the same type of response, with no detectable MRD (< 0.01), except 1 pt who shifted to PR. Finally, of the 2 pts in SD, 1 persisted in SD after 10 months from the beginning of the Bortezomib maintenance, while the other one progressed. Thus, to date, of the 11 pts entered in the study, 55% are sCR+CR+VGPR, with an overall response rate of 63%. It is noteworthy that the 3 pts who relapsed (at 3, 4, 16 mo from maintenance start) had chromosome 13 deletion at diagnosis. Considering that not all pts underwent 2nd ASCT, TTP was evaluated from 1st ASCT. In the Bortezomib group (median follow-up 26 mo; range: 15 – 33 mo), median TTP has not yet been reached, whereas in the control group (median follow-up 34 mo; range: 14 – 62 mo), median TTP was 13 mo (log-rank P<0.01) (Fig 1). Finally, none of the pts in the Bortezomib group experienced grade 3 or 4 haematologic toxicity and/or PN requiring dose reduction or discontinuation of the drug. ConclusionThe preliminary results of this single center study, even though limited to a small cohort of pts, suggest that Bortezomib as single agent in post-ASCT maintenance may improve the quality of previously achieved response and prolong TTP. However, these preliminary results need to be confirmed by a longer follow-up and a randomized multicenter study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rituximab Maintenenance Therapy in CD20+ B-Cell Non-Hodgkin-Lymphoma – Final Results of a Multicenter Prospective Randomised Phase II Study.

Abstract 1707Poster Board I-733 BackgroundClinical and pharmacokinetic data suggest that the effect of rituximab could be improved by prolonged exposure to the drug. To test for this hypothesis we performed a prospective randomized trial of rituximab maintenance therapy in patients (pts) with CD20+ B-cell Non-Hodgkin-Lymphoma. MethodsAfter completion of standard treatment pts with CD20+ B-cell lymphoma were randomized to either observation or maintenance therapy with rituximab (375 mg/m2) administered every 3 months for 2 years. Both pts after first line therapy and pts after relapse treatment were included in the study. Pts with aggressive lymphoma were enrolled if they had achieved a complete response (CR) after initial treatment. Pts with aggressive lymphoma with residual tumor mass underwent positron emission tomography (PET) and qualified for randomization if this examination showed no signs of tumor activity. Pts with indolent lymphoma were eligible for the study if at least a partial response (PR) was achieved. Primary endpoint of the study was event free survival (EFS), secondary endpoints were relapse rate (RR), relapse free survival (RFS) and overall survival (OS). EFS and OS were analysed using an asymptotic logrank test, RFS using a competing risk model and RR using Fisher's exact test. ResultsAfter recruitment of 171 pts the planned final analysis was performed on an intention to treat basis. Complete data sets of 163 pts were evaluable. 91 (62%) pts were male, median age was 58 years, 130 pts (80%) hat one previous therapy, 27 pts (17%) 2 previous therapies, 4 pts (2%) 3 previous therapies and 1 pt (1%) 4 previous therapies. At study entry, 120 pts (74%) were in CR, 2 pts (2%) in unconfirmed CR and 41 pts (25%) in PR. Histological subtypes included diffuse large cell lymphoma (67 pts), follicular lymphoma (35 pts), mantle cell lymphoma (18 pts), primary mediastinal lymphoma (16 pts), marginal zone lymphoma (7 pts), Burkitt's lymphoma (5 pts), and other lymphomas (15 pts). Age, sex, number of previous therapies, remission state and diagnoses were well balanced between the rituximab maintenance and the observation group (p>0.05). After a median follow up of 28 months, EFS (HR 0.50, 95% CI 0.23-1.09, p=0.037,) and RFS (HR 2.52, 95% CI 1.11-5.70 p=0.03) were superior for the maintenance group. In regards to diagnostic subgroups, EFS was in particular prolonged in pts with mantle cell lymphoma (p=0.055, one sided logrank test) and to a lesser extent in pts with follicular lymphoma (p=0.16) and diffuse large cell B cell lymphoma (p=0.18). Relapse occurred more often in the observation group than in the treatment group, however this effect was not significant (relapse rate observation group/treatment group = 2.31, 95% CI 0.86-6.75, p=0.08). There was no difference in OS between the two groups (p=0.74). Maintenance therapy was generally well tolerated: in 5 pts a WHO Grade 3 toxicity event occurred, which were arrhythmia, neuropathy, leucopenia (n=1 each) and infections (n=2). In one pt two WHO Grade 3 toxicities were observed (pain and infection). ConclusionRituximab maintenance therapy is feasible, safe and well tolerated and improves EFS in patients with CD20+ B-cell lymphoma. In this analysis, the benefit of rituximab maintenance was particularly striking in patients with mantle cell lymphoma. This study has been continued with an amendment including additional pts with mantle cell and diffuse large cell lymphoma. DisclosuresNo relevant conflicts of interest to declare.

Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab Results in Severe Infectious Toxicity in Previously Untreated CLL Patients Who Achieve a Complete Response (CR) after Fludarabine and Rituximab (FR) Induction Therapy: Interim Safety Analysis of the CALGB Study 10101.

Alemtuzumab (Campath-1H) is approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Given the increasing role of chemoimmunotherapy in the treatment of CLL, the Cancer and Leukemia Group B initiated a phase II study administering FR followed by alemtuzumab for remission consolidation to previously untreated, symptomatic CLL patients (pts). Pts received fludarabine 25 mg/m2 IV on days 1–5; rituximab 50 mg/m2 IV on day 1, 325 mg/m2 IV on day 3, and 375 mg/m2 IV on day 5 of cycle 1, and 375 mg/m2 IV on day 1 of cycles 2–6; every 28 days for up to 6 cycles. Four months after the last dose of fludarabine, pts with stable or responsive disease by NCI 96 response criteria received consolidation therapy with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, 30 mg on day 5, and 30 mg thrice weekly thereafter for 6 weeks. Pts received standard pneumocystis (PCP) and Varicella Zoster Virus prophylaxis and were monitored weekly for Cytomegalovirus (CMV) reactivation by PCR, antigen test, or hybrid capture. We report safety data on the first 51 pts who received alemtuzumab. Median age was 60 years (range, 23–82), and 75% were male. Of 34 pts who attained an NCI 96 partial response (PR) after FR induction, 9 (26%) experienced unacceptable toxicity to alemtuzumab, as defined prospectively by the study. Eight grade 3 toxicities (4 opportunistic infections, 3 CMV reactivation, 1 hemorrhagic cystitis), and 1 grade 5 EBV lymphoproliferative disorder were observed. In contrast, 17 pts had CR after FR induction and 8 (47%) had unacceptable toxicity. Complications included grade 3 infections in 3 pts (2 CMV, 1 cryptococcus) and 5 grade 5 infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia). These infections occurred both during therapy and for up to 16 months following therapy. Analysis of alemtuzumab pharmacokinetics and genomic tumor features is currently ongoing. Continuous real-time safety monitoring prompted a study amendment to prohibit further pts in CR after FR induction from receiving alemtuzumab consolidation. Accrual of new pts to the trial is complete. Only pts in PR or with stable disease after FR induction continue to receive alemtuzumab consolidation, with close monitoring for infectious and other toxicities. Detailed response and outcome data will be reported when all pts have completed therapy. We conclude that alemtuzumab cannot be safely administered as consolidation therapy to pts who achieve an NCI 96 CR following induction chemoimmunotherapy. The safety and feasibility of alemtuzumab consolidation for pts in PR after FR induction remains under study, and such therapy should not be pursued outside of a clinical trial due to concerns about serious infectious morbidity and mortality.

Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary results of a phase II study with circulating endothelial cell (CEC) monitoring

4570 Background: Effective therapy for pts with advanced HCC is still lacking. This phase II trial was designed to define efficacy of bevacizumab in HCC pts. Methods: Pts with unresectable HCC received bevacizumab at 5–10 mg/kg bimonthly. Prior treatment for HCC was allowed. Main ineligibility criteria included Child-Pugh score &gt; 7; CLIP score &gt; 3; recent (&lt; 6 months) thromboembolic event; and anticoagulation or anti-platelet therapy. Propranolol had to be prescribed in case of large esogastric varices. CEC, identified by a CD45- CD31+CD146+7AAD- phenotype by four-color flow cytometry, were measured at day (D) 1,3,15 and 46 after start of treatment. Results: Overall, 30 pts (27 men; median age, 65.5 years [range, 23–84]; histologically proven cirrhosis, 20 pts [Child-Pugh A5/A6/B7: 12/15/3; CLIP 0/1/2/3/4: 1/6/14/6/3] received a median of 6 cycles (range, 2–25; total, 234). As progressive disease (PD) was observed within 16 weeks in 12 pts after inclusion of the first 23 pts treated at 5mg/kg, subsequent pts (n=7) were treated at 10 mg/kg as planned by the protocol design. Of the 30 pts treated at either dose, 6 (20%) discontinued bevacizumab because of variceal hemorrhage (variceal banding successful in every case) (n=3); grade 3 transient ischemic attack (n=1); grade 3 hemorrhagic ascites (n=1); and grade 3 proteinuria (n=1). Grade 1–2 toxicities included fatigue, epistaxis, hypertension, and proteinuria. Among the 24 pts evaluable for efficacy, 3 (12.5%) had partial response (PR), and 13 (54%) had stable disease (SD) (&gt; 16 weeks in 7 pts) (disease control rate (DCR), 67%). Median baseline CEC level (n=21) was 14/ml (range, 0- 71), as compared to 5.5/ml (range, 0–15) in healthy subjects (n=20) and 16/ml (range, 0–179) in pts with various metastatic cancers (n=80). CEC levels increased more than two-fold at D3 in 11 (52%) among 21 pts; a dramatic drop was observed in all PR pts, as well as in a fraction (25%) of SD pts. Conclusions: Bevacizumab is relatively safe and provides an encouraging DCR in patients with HCC and compensated cirrhosis. Accrual is ongoing at the dose of 10 mg/kg. The predictive value of CEC will be presented at the meeting. [Table: see text]

Antitumor effects of sorafenib and sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC) who had prior therapy with anti-angiogenic agents

4597 Background: Sorafenib and sunitinib are multi-targeted kinase inhibitors (TKI’s) with clinical activity in mRCC. Their effect in mRCC pts refractory to prior anti-angiogenic agents is unclear. We investigated the anti-tumor effect of sorafenib and sunitinib in patients with mRCC who failed prior treatment with anti-angiogenic agents. Methods: Pts with mRCC receiving sorafenib and sunitinib on compassionate use trials were identified. Those pts who had received prior treatment with anti-angiogenic agents defined as thalidomide, lenalidomide, M200 (anti-α5β1 integrin monoclonal antibody), bevacizumab, AG013736, sunitinib or sorafenib were selected and their treatment response to current sorafenib or sunitinib evaluated. Results: Seventy-two pts (39 receiving sorafenib and 33 receiving sunitinib) were identified. Of these 72 pts, 23 pts (32%) had received prior anti-angiogenic therapy as defined above. Demographics included: 19 male and 4 female, median age 61 years (range 44 to 77). Thirteen pts (57%) are currently evaluable; the remainder are too early for assessment. Twelve pts (92%) demonstrated tumor reduction including 4 pts with objective partial response (PR); 8 pts had stable disease with tumor shrinkage ranging from 4 to 27% and 1 pt had disease progression. Of the 4 PR pts, prior therapy included M200 (1 pt), lenalidomide (2 pts) and sorafenib (1 pt). Of the 13 evaluable pts 4 had failed a prior TKI and received a subsequent TKI and all had evidence of tumor shrinkage to subsequent therapy (sunitinib followed by sorafenib, 1pt - 16% shrinkage, sorafenib followed by sunitinib 2 pts - 33.4% and 24% and AG013736 followed by sunitinib 1 pt - 12% ). Conclusion: Sorafenib and sunitinib have anti-tumor activity in mRCC pts who have received prior anti-angiogenic agents. [Table: see text]

Doxil and gemcitabine combination therapy for recurrent ovarian cancer: Results of a phase II trial

5090 Background: Phase I trials have established the combination of pegylated liposomal doxorubicin (Doxil [D]) and gemcitabine as a tolerable regimen for patients (pts) with recurrent malignancies. Response rates and durations to single agent therapies in recurrent ovarian cancer are disappointingly low enough to warrant investigation of combination therapies. Methods: Twenty-five pts with recurrent ovarian cancer were enrolled in a phase II trial of D 25mg/m2 day 1 with gemcitabine 650mg/m2 day 1 and 8. All pts were previously treated with carboplatin and taxol, and 11 pts had received a second platinum regimen for relapsed disease. Four pts were platinum refractory, four were platinum resistant, and 17(68%) were platinum sensitive with a mean of 14.5 (range 7 to 29) months since the last platinum therapy. The median number of prior chemotherapy regimens was 2 (range 1 to 4). All pts had measurable disease and radiographic responses were determined with CAT scans every three cycles. Results: Twenty-four pts completed 3 to 12 (mean 6) cycles of therapy, and one pt was lost to followup after cycle four. Objective responses were demonstrated in 16 (64%) pts. Seven pts achieved a complete response (CR) with a mean progression free interval (PFI) of 7 (range 6 to 18) months. Nine (36%) pts had a partial response (PR) and six (24%) pts demonstrated stable disease (SD). The PFI for both PR and SD pts was 5.4 (range 3 to 10) months. Three (12%) pts showed progression at cycle 3. Overall 22/25 (88%) pts demonstrated a clinical benefit with disease response or stabilization (17/17 platinum sensitive vs. 5/8 platinum resistant/refractory). Two pts with PR withdrew secondary to toxicity at 4 and 5 cycles (recurrent grade 4 (G 4) thrombocytopenia, palmar plantar erythrodysesthesia). There were no episodes of febrile neutropenia. Transient G 4 neutropenia was observed in 6 (24%) pts and G 4 thrombocytopenia in one. Conclusions: The combination of D and gemcitabine is an active regimen for recurrent ovarian cancer, with response rates that exceed those reported for either single agent. No significant financial relationships to disclose.