Salvage Therapy For Pts Research Articles

A phase II trial of carboplatin (C) and nab-paclitaxel (ABI-007-nab-P) in patients with unresectable stage IV melanoma: Final data from N057E

9055 Background: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). Nab-P is an albumin-bound paclitaxel with ability to bind SPARC (secreted protein acid rich in cysteine), that is overexpressed in MM and associated with poor prognosis. This study explores the clinical activity of the combination of nab-P and C in patients (pts) with stage IV melanoma and SPARC correlatives. Methods: A parallel phase II trial was conducted in pts with unresectable stage IV melanoma, who were either chemotherapy naïve (CN) or were previously treated (PT). A treatment regimen consisting of nab-P (100 mg/m2) and C (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs ≥35% in the CN group and ≤5% vs ≥ 20% in the PT cohort. Major eligibility criteria: ≥18 years of age, ECOG PS ≤2, adequate organ function, platinum or taxane naive, peripheral neuropathy < grade 2, and no untreated brain metastasis; no pregnant and/or nursing women. Tumor tissue was tested for SPARC and level 3 immunohistochemical staining was considered positive. Results: 76 pts (41-CN and 35 PT) enrolled from 11/2006 - 7/2007, 3 pts (2-CN, 1-PT) cancelled prior to starting treatment. The median number of cycles administered was 4 (range 1–18-CN and 1–10-PT). There were 11 (28.2%) confirmed responses (1 CR and 10 PRs) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) confirmed responses (3 PRs) in the PT cohort (90% CI: 2.5–21.3%). Median PFS was 4.5 months (CN) and 4.1 months (PT). Median OS was 11.1 months (CN) and 10.9 months (PT).The most common severe toxicities in both groups (CTCAE ≥ grade 3) included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting. PFS was not affected by SPARC positivity; however, based on limited data there is some evidence that OS may be longer with tumoral SPARC positivity (10.0 vs 12.8 mo; SPARC negative vs SPARC positive). Conclusions: The weekly combination of nab-P and C appears to be well tolerated with promising clinical activity as front line or salvage therapy in pts with MM. SPARC positivity may be associated with improved OS. No significant financial relationships to disclose.

Phase I/II Study of Rituxan (R) in Combination with Doxil (D) in Patients (pts) with Relapsing or Refractory B-Cell Lymphoma: Clinical Efficacy without Cardiac Toxicity.

In the past, the most common initial combination chemotherapy regimen used by most oncologists to treat B-cell lymphoma was the CHOP regimen. Although doxorubicin (DOX) is a major component of CHOP, it is associated with myelosuppression, alopecia, and potential cardiotoxicity. In vitro data has demonstrated synergistic activity between rituximab and certain drugs, including DOX. Because of D's unique liposomal encapsulation, delivery, and toxicity profile, it may prove to be a more effective, less toxic anthracycline to combine with R. A formal Phase I/II trial to evaluate the safety and efficacy of R+D in pts with relapsing B-cell lymphoma was undertaken. R (375 mg/m2/dose) was given on day 1 and D (30 mg/m2/dose) on day 3 on q 21 day cycles for 6 cycles. Thirty-six of 42 pts have been enrolled to date. Four pts (n=3 with aggressive histologies) progressed while on treatment and did not complete the planned 6 cycles of therapy; 1 pt has not completed therapy, but is a PR mid-treatment. Demographics: 19M:17F; Median age = 63 (range 35–83); Follicular lymphoma (FL) grade 1 or 2 (n=14); FL, grade 3 (n=7); SLL (n=5); de novo DLBCL (n=3); Transformed NHL (n=6); Mantle cell lymphoma (n=1); Median number of prior treatments = 2 (range 1–8); prior anthracycline exposure (n=24; 67%). Overall, R + D was very well-tolerated. Reversible grade 3 (n=8) or grade 4 (n=4) neutropenia was seen and responded to growth factor support. Reversible grade 3 thrombocytopenia was seen in 2 pts. Of note, grade 3 palmar/plantar erythrodysesthesia occurred only in 3 pts whom were non-compliant with instructions given to avoid this side-effect associated with D therapy. Overall response rate (ITT) = 64% (42% CR, 22% PR); responses were equally distributed between both indolent and aggressive histologies. Median time-to-progression (TTP) = 12 months (range 1M to 57+M); mean TTP = 17 months. Median TTP in CRs = 14 months (range 4M to 57+M); Median TTP in PRs = 5 months (range 1M to 17M). Fifteen of 24 (63%) pts with prior anthracycline exposure demonstrated objective responses (9 CR; 6 PR). No clinical cardiac toxicity has been seen and comparison of pre-Rx to post-Rx LVEF remained >50% in all pts completing therapy. D + R immunochemotherapy is a unique, well-tolerated, non-cardiotoxic and effective salvage therapy for pts with either indolent or aggressive relapsed B-cell lymphoma. An update of the completed database will be presented at the annual ASH meeting.

Combination Therapy of Bortezomib with Bendamustin in Elderly Patients with Advanced Multiple Myeloma. Clinical Observation.

Bortezomib(Bo) was approved for therapy of relapsed Multiple Myeloma (MM) in 2003-for use in Germany 2004. There is growing evidence that combination of Bo with conventional chemotharapy agents could improve MM patients’ (pts) outcome(P.Richardson ASCO 2004). Bendamustin(Ben) is widely used for MM chemotherapy in Germany. In weekly low dose regimen it is well tolerated and highly effective in therapy of low grade lymphoma in elderly (K.Bremer ASCO2003, Abstract 2410). Ben has no cross resistances with other cytostatic drugs used in MM therapy, in low dose regimen it is well tolerated, has low bone marrow toxicity and no renal toxicity. We reported results of the combination therapy of the first 17 pts 2 years ago. Because of very good tolerability and high response rates we established the combination in our institution as a salvage-therapy for pts with relapsed MM after at least 2 previous chemotherapies. Till now we treated 40 pts - all white European-21 women, 19 men- median age 66 years (range 51–86). All pts had relapsed MM with clinical symptoms such as anemia, bone pain, progressive bone disease, several of the pts had renal failure (1 on hemodialysis). Previous therapies - median 4-(range 2–10)- included Melphalan, Dexamethason, VAD and sim. combinations, Cyclophosphamide, Bendamustin, Thalidomide, Bortezomib mono and in 3 pts tandem HD Melphalan. Therapy-regimen: Bortezomib 1–1,3 m/sqm d 1,4,8,11, Bendamustin 60mg/sqm d 1,8, Dexamethason 3x8mmg p.o. d 1–3 and 8–10 if tolerated, Ondansetron 8 mg i.v. d 1,4,8,11- q3w until best response- median number of cycles 4 (range 2–6). Early responses with symptom relief at begin of second cycle were frequently observed. Results (outcome according to SWOG criteria): ORR 85%, very good PR 25%(normal electrophoresis, normal level of free light chains in serum and urine), PR 47,5%, MR 12,5%. Remission duration in pts with at least PR- 8 Months (range 2–26 months)-19 pts are still alive. Toxicity: comprised fatigue and mostly mild thrombocytopenia without bleeding, reversible within 1 week. 8 pts had neuropathy and required symptomatic therapy with Gabapentine- most of them pretreated with Thalidomide. 9 pts had herpes zoster before aciclovir 3x400 mg daily was administered as prophylactic therapy. Conclusion: The therapy with combination Bortezomib- Bendamustin is highly effective, safe and well tolerated. The therapy is feasible in out-patient setting. The response rates suggest that the drugs act at least additive. We think therefore that further studies are warranted.

Outcome following multiple lines of salvage chemotherapy prior to autologous stem cell transplant for relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

8120 Background: The standard of care for chemosensitive relapsed or refractory DLBCL is autologous stem cell transplant (ASCT). There is no standard approach for patients (pts) whose disease fails to respond to platinum-based salvage chemotherapy (pSC) although pts who undergo further salvage chemotherapy to demonstrate chemosensitivity may benefit from ASCT (Chen, et al, BMT 2002). We analyzed the overall response rate (ORR) to each line of salvage therapy for pts with relapsed or refractory DLBCL and the impact of the number of salvage regimens necessary to demonstrate chemosensitivity on overall and progression-free survival (OS and PFS) post-ASCT. Methods: We retrospectively reviewed our computerized database and charts between Jan 1/99 - Dec 31/05 and identified 203 pts relapsed after or refractory to anthracycline-based chemo treated with pSC. Pts typically received 2–3 cycles of pSC to assess chemotherapy sensitivity. Responding patients received etoposide 60 mg/kg and melphalan 160 mg/m2 supported by autologous PBSCs. Pts with stable or progressive disease following first line salvage chemotherapy (SC1) were offered alternate non-cross resistant second-line salvage chemotherapy (SC2) and proceeded to ASCT if chemosensitive. Results: Pt characteristics: Median age at time of salvage chemotherapy: 52 years (range 21–65); primary refractory: 48%; advanced stage disease at salvage: 50%; prior rituximab: 17%; prior radiation 26%. 119/203 pts did not respond to SC1, 81 pts received SC2 and 10 pts received 3 salvage regimens (SC3). ORRs to salvage were: SC1: 40%, SC2: 14%, SC3: 10%. Pts able to proceed to ASCT were: SC1: 37%, SC2: 14%, SC3: 0. With a median follow-up of 1.8 years, the 2-year OS post ASCT for the SC1 and SC2 groups was 69% and 56% respectively. The 2-year PFS post ASCT for the SC1 and SC2 groups were 58% and 40%. Conclusions: The ORR to platinum-based SC is low in this cohort of primary refractory/relapsed patients (40%), and only 14% of pts who received SC2 after pSC responded. Although some have prolonged PFS following SC2 and ASCT, additional strategies should be investigated in these patients. No significant financial relationships to disclose.

Final Results of a Phase II Study of Bortezomib (Velcade) in Combination with Liposomal Doxorubicin (Doxil) and Thalidomide (VDT) Demonstrate a Sustained High Response Rates in Patients (pts) with Relapsed (rel) or Refactory (ref) Multiple Myeloma.

Background: Tumor microenvironment (ME) plays an important role in MM. It is associated with disease progression, metastasis, and resistance to therapy. Therefore, targeting the ME and the tumor cell simultaneously may be an effective way to overcome resistance in pts with rel/ref MM.Aim: Orlowski et al reported improved anti-tumor responses when bortezomib (V) was combined with doxil (D) in pts with hematologic malignancies. We investigated clinically, this approach i.e., targeting the MM cell as well as its ME, using a combination of V, D and low-dose thalidomide (T) as salvage therapy for pts with rel/ref MM. Here we report the final results along with survival data of this phase II study.Methods: All pts with rel/ref disease were eligible for this study. V was given at 1.3mg/m2 (D1,4,15,18) and D at 20mg/m2 (D1,15) every 4 weeks with daily T (200 mg) for 4–6 cycles. SWOG criterion was used to assess response. Low-dose coumadin (1–2 mg po qd) was used for prevention of venous thromboembolism (VTE).Results: Twenty three pts (9M, 14F; median age −57 , range 43–79 yrs; 21MM, 2 WM) have been enrolled. All pts had Stage III disease, median b2M was 4.2 and median number of prior therapies were 5(range 1–6). Prior therapies included stem cell transplant(SCT) in (41%), T (41%), adriamycin(A) (65%) steroids (82%) and velcade (12%). 74% had refractory disease. Seventeen pts have completed at least 1 cyc and are available for toxicity and response evaluation. One pt died of sepsis prior to completing 1 cyc and 1 pt with PR was taken off study for non-compliance after 1 cyc. ORR was with 65%(CR+PR) with 23% CR all of whom were IFE negative. The Median Progression Free survival was 10.9 months with an median overall survival of 15.7 months. Toxicity: 2 pts developed Gr. II plantar-palmar erythrodysthesia (PPE) and 1 had Gr. III cellulitis. No VTE was noted. No significant non-hematologic Gr. III/IV toxicity were seen. Despite prior exposure to anthracycle, we did not noted any cardiotoxicity with D.No significant neuropathy was noted.Conclusions: Pt with rel/ref MM usually have aggressive disease with paucity of effective regimens. VDT is an effective salvage regimen. Final results show high response rates with 22% of the patients achieving complete (IFE−) remissions. Responses were noted regardless of type of prior therapy. VDT could be safely given in patients with renal failure/insufficiency. Venous Thromboembolism (VTE) does not appear to be a problem with low dose coumadin prophylaxis. Final results of this phase II study will be presented at the 48 th annual ASH meeting.

A Phase II Study of Velcade (V), Doxil (D) in Combination with Low-Dose Thalidomide (T) as Salvage Therapy for Patients (pts) with Relapsed (rel) or Refractory (ref) Multiple Myeloma (MM) and Waldenstorm Macroglobulinemia (WM): Encouraging Preliminary Results.

In MM, tumor microenvironment (ME) plays an important role in disease progression, dissemination, and development of resistance to therapy. Pts with rel/ref MM have limited treatment options. Therefore, targeting the ME simultaneously with malignant cells may be an effective way to overcome resistance in pts with rel/ref MM. Orlowski et al recently reported synergistic activity of V+D in patients with hematologic malignancies. A phase II trial initiated at our institute is exploring this approach, targeting the MM cell as well as its ME, using a combination of Velcade (V), Doxil (D) and low-dose thalidomide (T) as salvage therapy for pts with rel/ref MM. Pts with rel/ref disease are eligible for this study. V is given at 1.3mg/m2 (D1,4,15,18) and D at 20mg/m2 (D1,15) every 4 weeks with daily T (200 mg) for 4–6 cycles. SWOG criterion was used to evaluate response. Low-dose coumadin (1–2 mg po qd) was used for prevention of venous thromboembolism (VTE). Eighteen pts (7M, 11F; median age 56, range 44–80 yrs; 16MM, 2 WM) have been enrolled to date. All pts had Stage III disease, median b2M of 4.8 (nl range: 0–2.15) and median prior therapies 2 (range 1–7). Prior therapies included stem cell transplant in (46%), T (54%), adriamycin(A) (70%) and steroids (92%). Thirteen pts have completed at least 1 cyc and are available for toxicity and response evaluation. One pt died of sepsis prior to completing 1 cyc and 1 pt with PR was taken of study for non-compliance after 1 cyc. ORR was 100% (13/13) with 5PR and 8MR. All pts are currently continued on therapy. Toxicity: 2 pts developed Gr. II plantar-palmar erythrodysthesia (PPE) and 1 had Gr. III cellulitis. No VTE was noted. VDT is a highly active salvage regimen in pts with rel/refr MM. Responses were noted despite prior failure of steroids, T or A. It is well tolerated without any significant non-hematologic Gr. III/IV toxicity. VTE does not appear to be a problem. Updated results of this first cohort of pts will be presented at the annual ASH meeting.