Phase II Trial of Oblimersen Sodium (G3139), Dexamethasone (Dex) and Thalidomide (Thal) in Relapsed Multiple Myeloma Patients (Pts).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2400-2400
Author(s):  
Ashrof Z. Badros ◽  
Olga Goloubeva ◽  
Bashi Ratterree ◽  
Sabrina Natt ◽  
Aaron Rapoport ◽  
...  
Keyword(s):  
Gene Expression ◽  
Median Duration ◽  
Median Number ◽  
Mitochondrial Pathway ◽  
Pcr Analysis ◽  
Protein Levels ◽  
Duration Of Response ◽  
Clinical Responses ◽  
Pre Treatment ◽  
Number Of Cycles

Abstract Bcl-2 acts as an important regulator of the mitochondrial pathway of apoptosis and promotes resistance of MM cells to chemotherapy. The Bcl-2 antisense oligonucleotide G3139 specifically targets Bcl-2 and may enhance the anti-tumor efficacy of Dex and Thal. In this trial G3139 was administered at 5 mg to the first 3 Pts and then 7 mg/kg/d by IVCI for 7d of 21d cycle. On day 4, Pts started Dex 40 mg daily for 4 d and Thal 100-400 mg as tolerated. After 3 cycles, responding Pts continued G3139 on a 5-week cycle with Dex 20 mg x 4d and Thal at the tolerated daily dose for up to 1 yr with an optional second yr for responding Pts. Thirty-three Pts treated to date had the following characteristics: median age 60 yrs (range: 28- 76), 22 males; 16 Pts had complex karyotypes; 14 Pts had B2M > 2.5 g/dl; LDH >1.5 normal in 7 Pts; Cr >1.5 mg/dl in 6 Pts; platelets <100,000/ul in 4 Pts. Pts had received a median of 3 prior regimens (range 2-4) including auto-SCT. Seventeen Pts had received prior Thal for a median duration of 6.5 mos. (range 2–8); 11 had no response or progressed on Thal. G3139/Thal/Dex regimen was well tolerated. The median number of cycles per Pt was 8 (range: 1–16). Toxicities included reversible increase in Cr from a median of 1.2 (0.6–2.5) at baseline to 1.5 (range: 0.9–2) at cycle 6. G3139 dose was decreased (3–5 mg/kg/d) for Cr elevations in teh majority of Pts. Thrombocytopenia <100K occurred between cycle 1 and 2 (P= 0.008), and was reversible. Other toxicities (>grade 2) included fatigue, neutropenia, fever, electrolyte disturbance, muscle cramps, rash, hypotension, constipation and infections. Only 3 Pts maintained 400 mg/d of Thal, most Pts required dose reduction to 50–200 mg/d due neuropathy. Thirty Pts were evaluable for response; 24 Pts (80%) had documented responses, including 2 CR, 4 near-CR (+ immunofixation) and 12 PR; 6 had minimal response and 6 Pts had PD. The median duration of response is 13 mos. The estimated PFS is 12 mos and the median OS is 17.4 mo. The upper limits of the 95% confidence interval for PFS and OS have not been reached. At a median follow up of 1 yr (range 1.5–16.6 mo), 7 Pts had died and 26 are alive, of them 16 Pts continue on the study. Responding Pts had an early and significant increase in polyclonal IgM from a median baseline of 35.5 mg/dl (range: 8–75) to 94 (45–211) after cycle 3 (P=0.005), suggesting activation of the innate immune system. CD138+ cells were isolated from BM aspirates pre-treatment, and on d 4 or 7, and 28. Western blot analysis of Bcl-2 protein demonstrated demonstrated a decrease in Bcl-2 levels after normalization for protein loading by densitometry in 3 of 7 Pts with sufficient cells for analysis. The change of Bcl-2 protein levels did not correlate with response. Real time quantitative RT-PCR analysis was subsequently used to evaluate changes in Bcl-2 gene expression. Of 9 Pts evaluated, 6 demonstrated a significant decrease in Bcl-2 mRNA expression when normalized against GAPDH; 5 of them had a clinical response. In conclusion, G3139, Dex and Thal regimen is well tolerated in relapsed MM Pts. G3139 was associated with significant decrease in Bcl-2 gene expression in some Pts. G3139 appears to over-come resistance to Dex/Thal with impressive clinical responses in relapsed/refractory MM patients.

DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8541-8541 ◽  
Author(s):  
Adam D. Cohen ◽  
Suzanne Trudel ◽  
Sagar Lonial ◽  
Edward N. Libby ◽  
Hans Chulhee Lee ◽  
...  
Keyword(s):  
Partial Response ◽  
Safety Profile ◽  
Single Agent ◽  
Median Number ◽  
Blurred Vision ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Independent Review ◽  
Clinical Responses ◽  
Number Of Cycles

8541 Background: Patients with RRMM and HR cytogenetics have a poor prognosis and need effective therapies. In DREAMM-2 (NCT03525678), single-agent belantamab mafodotin (an immunoconjugate targeting B-cell maturation antigen) demonstrated clinically meaningful activity and a manageable safety profile in patients with heavily pretreated RRMM ( Lancet Oncol.2020). We present outcomes in patients with HR-cytogenetics (9-month follow-up). Methods: Patients with RRMM received single-agent belantamab mafodotin (2.5 or 3.4 mg/kg). For this post hoc analysis, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21+ (tested locally). Results: The median number of cycles was 3 (2.5: range: 1–15) and 4 (3.4: range: 1–14). Overall response rate (ORR; ≥partial response [PR] per independent review committee) was 27% in the 2.5 mg/kg group (22% with ≥very good partial response [VGPR]) and 40% in the 3.4 mg/kg group (27% with ≥VGPR). The median duration of response (DoR) was not reached in the 2.5 mg/kg group and was 6.2 months in the 3.4 mg/kg group. The most common adverse events ( > 30% in either group) were consistent with the overall population ( Lancet Oncol.2020): keratopathy (2.5: 59%;3.4: 79%), thrombocytopenia (2.5: 44%; 3.4: 65%), nausea (2.5: 27%; 3.4: 33%), anemia (2.5: 24%; 3.4: 42%), and blurred vision (2.5: 20%; 3.4: 42%). Conclusions: Patients with HR-cytogenetics maintain deep and durable clinical responses with single-agent belantamab mafodotin, comparable to that reported in the overall population. The safety profile remained consistent with previous reports. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

scholarly journals Using cfRNA as a tool to evaluate clinical treatment outcomes in patients with metastatic lung cancers and other tumors

2021 ◽  
Author(s):  
Luis E. Raez ◽  
Kathleen Danenberg ◽  
Daniel Sumarriva ◽  
Joshua Usher ◽  
Jacob Sands ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Response To Therapy ◽  
Liquid Biopsies ◽  
Blood Samples ◽  
Lung Cancers ◽  
Metastatic Lung ◽  
Clinical Responses ◽  
Pre Treatment ◽  
Actin Expression

Aim: We report an exploratory analysis of cfRNA as a biomarker to monitor clinical responses in non-small cell lung cancer (NSCLC), breast cancer, and colorectal cancer (CRC). An analysis of cfRNA as a method for measuring PD-L1 expression with comparison to clinical responses was also performed in the NSCLC cohort. Methods: Blood samples were collected from 127 patients with metastatic disease that were undergoing therapy, 52 with NSCLC, 50 with breast cancer, and 25 with CRC. cfRNA was purified from fractionated plasma, and following reverse transcription (RT), total cfRNA and gene expression of PD-L1were analyzed by real-time polymerase chain reaction (qPCR) using beta-actin expression as a surrogate for relative amounts of cfDNA and cfRNA. For the concordance study of liquid biopsies and tissue biopsies, the isolated RNA was analyzed by RNAseq for the expressions of 13 genes. We had to close the study early due to a lack of follow-up during the Covid-19 pandemic. Results: We collected a total of 373 blood samples. Mean cfRNA PCR signals after RT were about 50-fold higher than those of cfDNA. cfRNA was detected in all patients, while cfDNA was detected in 88% of them. A high concordance was found for the expression levels of 13 genes between blood and solid tumor tissue. Changes in cfRNA levels followed over the course of treatments were associated with response to therapy, increasing in progressive disease (PD) and falling when a partial response (PR) occurred. The expression of PD-L1 over time in patients treated with immunotherapy decreased with PR but increased with PD. Pre-treatment levels of PD-L1 were predictive of response in patients treated with immunotherapy. Conclusion: Changes in cfRNA correlate with clinical response to the therapy. Total cfRNA may be useful in predicting clinical outcomes. PD-L1 gene expression may provide a biomarker to predict response to PD-L1 inhibition.

scholarly journals The Efficacy of Cladribine (2-CdA) in Advanced Systemic Mastocytosis

2020 ◽  
Vol 36 (4) ◽  
pp. 661-666 ◽  
Author(s):  
Grzegorz Helbig ◽  
Anna Koclęga ◽  
Władysław B. Gaweł ◽  
Martyna Włodarczyk ◽  
Marek Rodzaj ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Systemic Mastocytosis ◽  
Median Number ◽  
Hemoglobin Level ◽  
Median Dose ◽  
Skeletal Involvement ◽  
Duration Of Response ◽  
Hematological Neoplasm ◽  
Number Of Cycles

Abstract Systemic mastocytosis (SM) is a rare clonal disorder with multi-organ involvements and shortened life expectancy. To date, no curative treatment for SM exists. Cladribine (2-CdA) is a purine analogue showing activity against neoplastic mast cells and its use was found to be effective in some patients with SM. Nine patients (six males and three females) with advanced SM at median age of 63 years (range 33–67) who received at least one course of 2-CdA were included in a retrospective analysis. Study patients were classified as having aggressive SM (ASM; n = 7) and SM with an associated hematological neoplasm (SM-AHN; n = 2). The “C” findings were as follows: (1) absolute neutrophil count (ANC) < 1 × 109/l (n = 1) and/or hemoglobin level < 10 g/dl (n = 4) and/or platelet count < 100 × 109/l (n = 4); (2) hepatomegaly with ascites (n = 4); (3) skeletal involvement (n = 2); (4) palpable splenomegaly with hypersplenism (n = 3) and (5) malabsorption with weight loss (n = 5). Treatment consisted of 2-CdA at dose 0.14 mg/kg/day intravenously over a 2-h infusion for 5 consecutive days. Median dose per cycle was 45 mg (range 35–60). Median number of cycles was 6 (range 1–7). Overall response rate (ORR) was 66% (6/9 pts) including three partial responses and three clinical improvements. ORR was 100% and 66% for SM-AHN and ASM, respectively. Median duration of response was 1.98 years (range 0.2–11.2). At the last contact, five patients died, four have little disease activity, but remain treatment- free. 2-CdA seems to be beneficial in some patients with SM, however the response is incomplete.

Phase II trial of sorafenib (bay 43–9006) in patients with advanced anaplastic carcinoma of the thyroid (ATC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6058-6058 ◽  
Author(s):  
G. Nagaiah ◽  
P. Fu ◽  
J. K. Wasman ◽  
M. M. Cooney ◽  
C. Mooney ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Median Duration ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Median Number ◽  
Anaplastic Carcinoma ◽  
Open Label ◽  
Open Label Phase ◽  
Number Of Cycles

6058 Background: Sorafenib (bay 43–9006) is an oral, small molecule tyrosine kinase inhibitor of the raf-1 protein kinase receptor, VEGFR2 and PDGFR-β with antiangiogenic properties. We are conducting an open label, phase II study of sorafenib in patients with biopsy-proven ATC to evaluate if its objective response rate is >20% and to further characterize its safety profile. Methods: Patients with progressive ATC, after cytotoxic chemotherapy with or without radiation were given sorafenib, on a fixed dosing schedule of 400 mg PO bid on 28-day cycles. Treatment was continued until disease progression, unacceptable toxicity or patient refusal. Response was evaluated every 8 weeks with body scans using RECIST criteria. We employed a 2-stage study design: if none of the first 18 patients respond the study is terminated, otherwise accrual is continued to a total of 36 patients at which point if ≤3 of the patients respond, the treatment option is rejected. Results: To date 16 patients (10 male) have enrolled in the study. Median age is 55 years; with (range 28–79). Median time on study is 2 months. Median number of cycles given is 2 (range 1–27). Two of 15 evaluable patients (13%) have partial response (PR) and 4 patients (27%) have stable disease (SD). Median duration of PR/SD is 5.1 months (range 1–24.7months). Median time to progression is 1.5 months. Median duration of survival is 3.5 months (range 1–26 months). All patients at time of reporting are deceased. Most common toxicities are lymphopenia (81%) and fatigue (62%). Grade 3 toxicities include lymphopenia (25%), rash with desquamation, weight loss, and chest pain (all 12%). Grade 4 toxicities include dyspnea (6%) and lymphopenia (6%). There has been no significant cardiovascular toxicity. One patient died on study with rapidly progressive disease. Conclusions: Sorafenib demonstrates objective tumor response in the first 15 evaluable and pretreated patients with advanced ATC. This trial is ongoing and supported in part by NIH grant nos. CA62502. [Table: see text]

MEDI3726, a prostate-specific membrane antigen (PSMA)-targeted antibody-drug conjugate (ADC) in mCRPC after failure of abiraterone or enzalutamide.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Johann S. De Bono ◽  
Mark T. Fleming ◽  
Judy Sing-Zan Wang ◽  
Richard Cathomas ◽  
Marna Williams ◽  
...  
Keyword(s):  
Phase 1 ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Median Number ◽  
Antibody Drug Conjugate ◽  
Starting Dose ◽  
Duration Of Response ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Composite Response

99 Background: MEDI3726 is an ADC targeting PSMA. Once bound to PSMA and internalized, the released pyrrolobenzodiazepine dimer toxin crosslinks DNA and triggers cell death. This phase 1 study evaluated the safety and efficacy of MEDI3726 in mCRPC after failure of abiraterone and/or enzalutamide and a taxane-based therapy. Methods: The starting dose was 0.015 mg/kg MEDI3726 IV Q3W until disease progression or unacceptable toxicity. Dose escalation used a modified toxicity probability interval algorithm (mTPI). The primary objectives were safety, adverse events (AEs) and dose-limiting toxicities (DLTs) and to determine the maximum tolerated (MTD) or administered (MAD) dose. Secondary objectives included antitumor activity, pharmacokinetics and immunogenicity. The endpoint for activity was composite response: confirmed response by RECIST v1.1, and/or PSA decrease of ≥ 50% after ≥ 12 wks, and/or confirmed conversion in circulating tumor cell count, defined as a decrease from ≥ 5 to < 5 cells/7.5 mL. Efficacy analyses were based on Prostate Working Group Criteria. Mutational profiles were evaluated in ctDNA. Results: As of Sept 27 2019, 33 pts received MEDI3726. Median age was 71.0 yr. Median number of prior regimens was 4. Median follow-up was 5.4 mo. Drug-related AEs occurred in 30 (90.9%), being grade 3/4 in 15 (45.5%), serious in 11 (33.3%) and causing discontinuation in 13 (39.4%). There were no drug-related deaths. One pt at 0.3 mg/kg had a DLT of Grade 3 thrombocytopenia. No MTD was identified per mTPI; the MAD was 0.3 mg/kg. MEDI3726 had nonlinear PK with a short t1/2 (0.3–2 d). Three pts (15.8%) at baseline and 6 (33.3%) post-baseline had antidrug antibodies, with no correlation to PK exposure. Composite response rate across all doses was 2/33 (6.1%). Time to response was 0.3 mo; duration of response was 1.8–3.8 mo. Median progression-free survival was 3.9 mo and median overall survival was 10.6 mo. Conclusions: An MTD was not identified, but drug-related AEs (skin toxicities and effusions) prevented raising the dose over 0.3 mg/kg and limited the number of cycles. Responses were seen at higher doses, but were not durable as pts discontinued due to drug-related AEs. Clinical trial information: NCT02991911.

A non-randomized phase II study of sequential irinotecan (CPT) and flavopiridol (F) in patients (pts) with advanced hepatocellular carcinoma (HCC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4148-4148 ◽  
Author(s):  
G. K. Abou-Alfa ◽  
R. D. Carvajal ◽  
K. Y. Chung ◽  
R. A. Ghossein ◽  
M. Capanu ◽  
...  
Keyword(s):  
Phase I ◽  
Median Number ◽  
Advanced Hepatocellular Carcinoma ◽  
Wild Type ◽  
Advanced Hcc ◽  
Progression Of Disease ◽  
Wild Type P53 ◽  
Pre Treatment ◽  
Number Of Cycles ◽  
Induced Apoptosis

4148 Background: F is a CDK inhibitor which potentiates CPT- induced apoptosis. In a phase I trial of CPT 100mg/m2 followed 7 hours later by F given over 1 hour weekly for 4 out of 6 weeks (Shah, Clin Can Res 2005), 2 pts with advanced HCC had stable disease (SD) for 14+ months. In the same phase I study, patients who were p53 wild-type (negative p53 staining), and whose p21 remained stable or was non-detectable on the post-treatment biopsy, were noted to have SD or a partial response. Methods: Pts with advanced HCC, no prior systemic therapy, Child’s-Pugh score A, B7 or B8, and KPS ≥ 70%, received 100 mg/m2 of CPT, followed 7 hours later by 60 mg/m2 of F over 1 hour weekly for 4 out of 6 weeks. The trial had a two stage design, with a planned accrual of 30 pts. The primary endpoint was TTP. Tumor response was assessed every 2 cycles using revised WHO criteria. p53 immuno-staining was performed on pre-treatment paraffin preserved tissues. A cut-off of 20% defined positive mutant versus negative wild-type p53 status. Results: 16 pts were enrolled: median age 64 (range 26–84), KPS 80% (70–90%), and 10 males/6 females. 13 pts received therapy, two progressed before starting, and one patient (pt) was excluded because pathology re-review did not confirm HCC. 1 pt was excluded because of consent withdrawal after first dose of therapy. This pt was included in the toxicity analysis. The median number of cycles given was 2 (range 1–8 cycles). Grade 3 and 4 toxicities included dehydration (4: 30%) diarrhea (2: 15%) febrile neutropenia (6: 46% - 4 events in one pt) and fatigue/weakness (3: 23%). Therapy had to be discontinued in 2 pts because of toxicity. TTP was 2.6 months (95% CI 2.43–8.42). One patient had SD for over a year, 8 had progression of disease (POD), and 4 came off study because of toxicity. Mutational p53 was evaluated in 7 pts. The pt with SD had wild type p53. Three pts with POD had mutant p53, while the other 3 had wild type 53. Conclusions: CPT followed by F is an ineffective therapy for HCC. This therapy was relatively poorly tolerated, likely contributed to by underlying cirrhosis in HCC, but similar to our experience of CPT in HCC. While p21 level pre and post therapy is lacking, the wild type p53 of the patient with SD maybe a predictor of response in HCC where p53 mutations are common. No significant financial relationships to disclose.

Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8600-8600 ◽  
Author(s):  
Preet Paul Singh ◽  
Wilson I. Gonsalves ◽  
Vinay Gupta ◽  
Francis Buadi ◽  
Martha Lacy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Median Duration ◽  
Median Overall Survival ◽  
Median Number ◽  
Infusion Therapy ◽  
P Value ◽  
Short Term Mortality ◽  
Number Of Cycles ◽  
Clinical Records ◽  
Count Recovery

8600 Background: The combination of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDTPACE) was developed as an intense regimen for disease control prior to tandem transplantation for multiple myeloma (MM) in total therapy protocols. The regimen is very effective in this setting, and since has also been used in the relapsed setting. We examined the outcomes of a set of patients undergoing VDTPACE therapy for relapsed MM at our institution. Methods: We identified 71 patients who received VDTPACE for relapsed MM, at Mayo Clinic from 7/2006 to 7/2012. Plasma cell leukemia was excluded. All data was extracted from clinical records. Results: The median age of patients was 59 years (range, 39-80); 48 (67.6%) were male. The median time from diagnosis to initiation of VDTPACE was 38.2 months (range, 2-125). The median number of cycles given was 1 (range, 1-9). The overall response rate after one cycle was 57.1% (14.3% VGPR, 22.2% PR and 20.6% MR) in the 63 patients in whom the response was evaluable. The median overall survival (OS) post-VDTPACE was 8.2 months (95% CI, 5.7-10.9). Eighteen (25.4%) patients went on to autologous stem cell transplantation (SCT), and 7 (9.9%) received matched allogeneic SCT following VDTPACE, and the median OS post-VDTPACE was significantly longer for these groups compared to those who were not transplanted (15.3 and 20.5 months, respectively vs 5 months, p-value <0.001). Thirty eight of 66 (57.6%) patients were rehospitalized after initial admission for infusion therapy for a median duration of 6 days (range, 1-26). The median platelet and red cell transfusions were 4 (range, 0-21) and 5 (range, 0-22) units, respectively. Renal toxicity was seen in 13/62 (21%) patients and 27/65 (41.5%) patients developed neutropenic fever. The median duration to absolute neutrophil and platelet count recovery was 18 (range 12-42) and 27 (range, 12-42) days, respectively. Three (4.2%) patients died within 30 days and 11 (15.5%) within 8 weeks of initiating VDTPACE. Conclusions: VDTPACE is an effective therapy in relapsed MM but is associated with significant morbidity and short-term mortality. It appears to be more effective when followed by an autologous or allogeneic SCT.

Cyclophosphamide with (+)/without (-) fluorouracil followed by subcutaneous or intravenous interleukin-2 in solid tumors: An off-label experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14621-e14621 ◽  
Author(s):  
Giovanni Lo Re ◽  
Francesco Lo Re ◽  
Paolo Doretto ◽  
Alessandro Del Conte ◽  
Maria Amadio ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Immune Surveillance ◽  
Interleukin 2 ◽  
Suppressor Cells ◽  
Median Number ◽  
Control Activity ◽  
Relevant Role ◽  
Duration Of Response ◽  
Number Of Cycles

e14621 Background: primary and acquired resistance cause treatment failure to several agents. Recently it is emerging the role of immune surveillance in the control of tumor progression. The immune tolerance correlates with disease progression and FOXP3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) play a relevant role in immunosuppression. Cyclophosphamide (C) and Fluorouracil (FU) seems to reduce these cell populations. Methods: Objective: safety, feasibility, pain control, activity and impact on immune system (Neutrophil/Lymphocyte (N/L), Platelet/L (P/L), Tregs %, Monocytes (M)(103/μL) count.Treatment: 1) C 300 mg/sqm +/- FU 500 mg/sqm day (d) 1, Interleukin-2 (IL-2) 18 MUI/sqm intravenous continuous infusion (i.v.c.i) d 3-5, 17-19 q 29 or 2) C 300 mg/sqm + FU 500 mg/sqm day d 1, IL-2 4.5 MUI subcutaneous (s.c) d 3-6, 17-20 q 29 for 2 cycles. Stable or responding patients (pts) continue therapy for three cycles. Results: from February 2014 to December 2016, 13/14 pts were treated. M/F:1/1. Median age was 68 years and median PS 1 (range 0-2). The primary tumor was bladder, liver, pancreas, neuroendocrine carcinoma and ovary in 2, melanoma, prostate, GIST and breast in 1 pt respectively. Sites of metastases were: lung in 4, liver in 9, lymph’nodes in 9, bone in 5 and spleen in 1 pt respectively. Previous therapy: 1- 2 in 6, ≥ 3 in 8. Six and 7 pts performed treatment 1, 2 respectively. Median number of cycles administered was 2 (range 1-3). Median basal and post-treatment N/L, P/L, M and Treg values were 2, 130, 0.49, 2,9% and 2, 94, 0.55, 10.5%. Pain improvement was obtained on 7/8 pts. The toxicity was manageable as for i.v.c.i as for s.c administration. In addition to universal capillary like syndrome, G3-4 toxicities were diarrhea, bleeding, anemia in 2, proteinuria in 1 pt respectively. Response: 3 PR (2 HCC, 1 pancreas), 2 SD, 4 PD, 5 unevaluable. The duration of response was 2+ and 3 months in 2 HCC pts and 8+ months in pancreatic pt. The crude median PFS and OS was 1 (range1-8+) and 2+ (range 1-18) months Conclusions: C- FU- IL-2 can be considered safe, feasible and meanly active in heavy pretreated pts. Except P/L, no reduction on Tregs, M counts and N/L was observed.

Response Rates of Phase 2 and Phase 3 Trials of Decitabine (DAC) in Patients with Myelodysplastic Syndromes (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2515-2515 ◽  
Author(s):  
Hussain I. Saba ◽  
Michael Lübbert ◽  
P.W. Wijermans
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Median Duration ◽  
Response Rate ◽  
Response Rates ◽  
Median Number ◽  
Phase 2 ◽  
Phase 3 ◽  
Overall Response ◽  
Number Of Cycles

Abstract Background: MDS is characterized by ineffective hematopoiesis, resulting in cytopenias with dysplastic morphology of peripheral blood cells and bone marrow. Decitabine (Dacogen™ DAC) is a cytosine analog that reverses aberrant DNA methylation, leading to re-expression of silenced tumor suppressor genes. Due to the requirement for DNA synthesis and subsequent demethylation, decitabine may require prolonged administration to achieve maximum benefit. Overall response rates (ORR) (CR+PR) from 1 pivotal Phase 3 (D-0007) and 3 supportive Phase 2 trials (91–01, 95–11 and 97–19) in patients with intermediate and high risk MDS receiving DAC are being presented. Methods: The Phase 2 trials were open-label and single-arm, with a minimum of 4 treatment cycles and a maximum of 8 cycles, while the D-0007 was a 1:1 randomized comparison of DAC plus supportive care (SC) vs. SC alone, with a maximum of 10 cycles of therapy. The D-0007 study design dictated that patients be removed from therapy following 8 cycles of decitabine if CR was not achieved, and 6 cycles in the absence of PR. Patients who maintained a CR for 2 cycles were removed from therapy. Results: A total of 271 unique patients were exposed to DAC in the studies (n= 89 in D-0007, n=29 in 91–01, n = 66 in 95–11, n = 87 in 97–19). Patients receiving DAC had similar demographics and disease characteristics in all trials. Responses were observed in all IPSS and FAB subgroups. The percent of patients classified as intermediate-2 and high risk (according to the International Prognostic Scoring System) in the Phase 3 trial was 69% vs. 72% in the Phase 2 trials. By intent-to-treat analysis, the ORRs were 45%, 26%, and 26% respectively, for the Phase 2 trials. These results were corroborated in the Phase 3 trial, where the response rates were evaluated according to the more robust International Working Group MDS criteria, following a blinded, centralized bone marrow review. The D-0007 overall response rate was 17% for DAC (9% CR, 8% PR) vs. 0% for SC (p<0.001). Responses were durable, lasting a median of 266 days. The 95–11 and 97–19 response rates were also centrally reviewed, while 91–01 responses were investigator-assessed. In the 91–01 trial, the ORR was 45% (28% CR, 17% PR) with a median duration of response of 217 days, the 95–11 ORR was 26% (21% CR, 5% PR) with a median duration of 250 days, and the 97–19 ORR was 26% (22% CR, 5% PR) with a median duration of 146 days. Hematologic improvement (HI) was also evaluated according to varied criteria in conjunction with the response rates in all 4 studies; 12 patients (13%) had HI in D-0007, 2 patients (7%) in 91–01, 8 patients (12%) in 95–11, and 13 patients (15%) in 97–19. The D-0007 trial design dictated that patients who maintained a CR for 2 cycles be removed from therapy. As a result, the median number of cycles delivered was 3, with only 48% of patients receiving ≥4 cycles. In the Phase 2 studies, the median number of cycles is clearly higher (median 4), with the majority of patients receiving at least 4 cycles and approximately one-third of patients receiving ≥6 cycles. Conclusion: While response rates of ≥17% were demonstrated in these trials, the optimization of hypomethylating agents for maximum efficacy is very likely to include prolonged therapy, which may correlate with increases in response rate and duration.

Benefits of pembrolizumab in progressive radioactive iodine refractory thyroid cancer: Results of the AcSé Pembrolizumab Study from Unicancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6082-6082
Author(s):  
Sophie Leboulleux ◽  
Yann Godbert ◽  
Nicolas Penel ◽  
Segolene Hescot ◽  
Christelle De La Fouchardiere ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Median Duration ◽  
Radioactive Iodine ◽  
Tumor Response ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Open Label ◽  
Multicentric Study ◽  
Duration Of Response

6082 Background: AcSé Pembrolizumab is a Phase II, non-randomized parallel arm, open-label, multicentric study from Unicancer investigating the efficacy and safety of pembrolizumab monotherapy in different cohorts of patients with rare cancers (NCT03012620). Here we report the first results of pembrolizumab in the radioactive iodine refractory thyroid cancer cohort. Methods: Main inclusion criteria were progressive radioactive iodine refractory (RAIR) thyroid cancer (TC) resistant to standard treatment, age > 18, ECOG PS≤1. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response (OR) rate according to RECIST v1.1 by investigator. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Results: 43 patients (21 female, mean age 64.8 years; range 40-86) with TC (27 patients with differentiated TC (DTC) [papillary: 7; follicular: 14: oncocytic: 5 poorly differentiated: 1] and 16 patients with anaplastic TC (ATC)) were included from September 2017 to December 2020. The median number of previous systemic treatment lines was 2 (range, 0-7) in DTC and 2.5 (range, 1-4) in ATC. The median number of pembrolizumab cycles was 4 (range, 1-35). The median follow-up was 5.9 months (range: 22 days-22.9 months) for DTC and 2.7 months (range: 3 days- 24.4 months) for anaplastic TC. For DTC the best tumor response was partial response (PR) in 3 (11.1%) patients and stable disease (SD) in 5 (18.5%). Median duration of response was 2.5 months (range: 5 days-7.2 months). The median PFS was 2.6 months, the 6-month PFS was 16.9 %. The median OS was 12.7 months with a 6-month OS of 73.3%. For ATC the best tumor response was PR in 3 cases (18.8 %) and SD in 1 case (6.2 %). Median duration of response was 1.6 months (range: 2 days-7.2 months). The median PFS was 2.3 months, the 6-month PFS was 33.8 %. The median OS was 3.6 months with a 6-month OS of 32.9%. Treatment emergent adverse event included 9 Grade 1-2, 20 Grade 3 (3 being considered as related and 17 as not related) and 1 Grade 4 (sepsis, unrelated). Overall, the toxicity profile was similar to that observed in other cancers. Conclusions: The response rates observed under pembrolizumab is low in DTC and not negligible in ATC, but with a short duration of response. Clinical trial information: NCT03012620.

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