Phase II Study of Enzastaurin in Patients with Follicular Lymphoma: Updated Final Clinical Results and Immunohistochemical Correlations

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 777-777
Author(s):  
Lee Schwartzberg ◽  
Robert Hermann ◽  
Ian W. Flinn ◽  
Douglas Flora ◽  
Eric D. Hsi ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
International Prognostic Index ◽  
Single Agent ◽  
Clinical Results ◽  
Qtc Interval ◽  
Correlative Study ◽  
Study Results

Abstract Abstract 777 Background: Protein kinase C β (PKCβ) is critical for B-cell signaling and survival. Over-expression of PKCβ is implicated in the pathogenesis of follicular lymphoma (FL). Enzastaurin (ENZ), an oral serine/threonine kinase inhibitor, targets the PKCβ and PI3K/AKT pathways to inhibit tumor cell proliferation, induce apoptosis, and suppress tumor-induced angiogenesis. Reported here are the final clinical and correlative study results from a phase II study. Methods: This was an open-label, single-arm, study of patients (pts) with hiastologically confirmed grade 1/2 and stage III/IV measurable FL. Pts were either chemonaive or relapsed after 1 chemotherapy regimen or single-agent rituximab. Pts received 500 mg oral ENZ once daily (1125-mg loading dose on D1) ≤ 3 years or until progression, withdrawal, or toxicity. The primary endpoint was response rate (RR). Secondary objectives included progression-free survival (PFS), duration of response (DoR), and safety. Pre-treatment samples were used for correlative research. Staining was performed for BCL2, BCL6, CD10, Ki67, FOXP1, FOXP3, CD20, MUM1, CD68, and PD1 expression. ENZ-specific biomarkers investigated by immunohistochemistry (IHC; standard H scores range 0–300) included PKCβ2, PTEN, pS6, pGSK3β, and pCREB. Logistic/Cox regression determined the statistical correlation between clinical outcomes (RR or PFS) and IHC for each marker. All tests of association were conducted at a 2-sided α = 0.05. Clinical Results: Sixty-six pts (23 male, 43 female; median age 62 years \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(3382\) \end{document}) were enrolled. Based on FL International Prognostic Index, 12% had low-risk disease (0-1 risk factors [RF]); 55%, intermediate-risk disease (2 RFs); and 33%, high-risk disease (3-5 RFs). Forty-six pts (69.7%) were chemonaive and 20 pts (30.3%) had ≥ 1 prior chemotherapy. The median overall exposure was 10.8 months (mo; 1–57 mo). Of 58 pts who received ≥1 dose of ENZ, 2 (3.4%) had complete response, and 15 (25.9%) had partial response (overall RR = 29.3%). The median PFS was 15.2 mo (95% confidence interval [CI] 11.1–25.7 mo). DoR median was 20.5 mo (95% CI 9.1–31.5 mo). Seven pts (10.6%) discontinued treatment due to adverse events (AEs), of which 5 (7.6%) were possibly drug related: bronchitis, prolonged QTc interval, abdominal distention, colitis, and skin rash. Four pts (6.1%) had drug-related serious AEs: grade (Gr) 3 bronchitis, Gr 2 vision, Gr 2 diarrhea, Gr 2 pancreatitis. There were no drug-related deaths. To date, 5 pts remain on treatment and have been on treatment 3.5–5 years. Correlative Results: Tumor tissue was obtained from 28 pts. Patient demographics and overall RR were well balanced between protocol and correlative study populations. No significant associations with RR or PFS were observed for any FL-specific markers. Significant associations were observed between low cytoplasmic PKCβ2 and increased RR (median H score cutpoint 151.5, odds ratio (OR) [95%CI] = 0.027 [0.001-0.656], p=0.027) (Table 1, Figure 1). Significant associations were also observed between PFS and both cytoplasmic PKCβ2 and cytoplasmic pS6 using median H score cutpoint (Table 1). Conclusions: ENZ has clinical activity and is well tolerated in pts with grade 1/2 FL. Low cytoplasmic PKCβ2 was significantly associated with increased RR and longer PFS; high cytoplasmic pS6 was significantly associated with longer PFS. The correlative results are hypothesis generating given the study's size and nonrandomized nature. Disclosures: Hermann: Eli Lilly and Company: Research Funding. Hsi:Eli Lilly and Company: Research Funding. Hamid:Eli Lilly and Company: Employment. Myrand:Eli Lilly and Company: Employment. Lin:Eli Lilly and Company: Employment. Thornton:Eli Lilly and Company: Employment. Shi:Eli Lilly and Company: Employment. Nguyen:Eli Lilly and Company: Employment.

scholarly journals Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 814-814
Author(s):  
Craig A. Portell ◽  
Opeyemi Jegede ◽  
Nina D. Wagner-Johnston ◽  
Grzegorz S. Nowakowski ◽  
Christopher D. Fletcher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Single Agent ◽  
Tumor Burden ◽  
Type I ◽  
High Tumor Burden ◽  
Grade 3

Abstract Background: Chemoimmunotherapy is considered standard initial therapy for follicular lymphoma (FL) with high tumor burden (HTB). Obinutuzumab and Bendamustine (OB) with maintenance Obinutuzumab (mO) is considered a standard therapy for the frontline treatment of HTB FL (GALLIUM, Marcus et al, NEJM 2017). Venetoclax (VEN), an oral BCL2 inhibitor, is an attractive target in FL given the high BCL2 expression; though single agent activity has been disappointing (Davids et al. JCO 2017). BCL2 inhibition is thought to be synergistic with chemotherapy. Thus, the PrE0403 study evaluated the OB-VEN combination in frontline HTB FL. Here we present end of induction (EOI) outcomes. Methods: The primary objective of this Phase II study was to estimate the complete remission (CR) rate at EOI. Potential participants must have had a histologically confirmed diagnosis of FL grade 1, 2, or 3a with HTB defined by GELF or high risk defined by FLIPI-1 criteria. They must have had adequate performance status and organ function. Notably, creatinine clearance must have been ≥50 mL/min. Participants must have not had prior treatment for FL. Eligible participants were treated with Bendamustine IV 90 mg/m2 Day (D) 1 & 2, Obinutuzumab IV 100 mg D1, 900 mg D2, 1000 mg D8 and D15 of Cycle (C) 1 then D1 of each cycle, and VEN 800 mg orally daily D1-10 every 28 days for 6 total cycles. Due to a high rate of laboratory tumor lysis syndrome (TLS) during C1 in the first 21 patients, VEN was removed from C1 and given in C2-6 only. Participants with a CR at EOI were treated with mO IV 1000 mg D1 every 8 weeks for 2 years. Those with a partial response (PR) or stable disease (SD) were treated with mO as well as VEN 800 mg orally daily for 2 years. Pneumocystis jiroveci Pneumonia (PJP) and antiviral prophylaxis was required as was G-CSF support. Response was assessed via Lugano Criteria at EOI including PET/CT and bone marrow assessment. Adverse Events (AEs) were evaluated using CTCAE v5.0. To be considered promising, OB-VEN should improve the null hypothesis CR rate of 50% (OB) to 65%. With an 85% power and a one sided 15% type I error, 56 participants would be needed with an estimated 51 eligible. Support for the study was from Genentech, Member of the Roche Group. Results A total of 56 participants were enrolled and treated between 12/2017 and 11/2020; baseline characteristics are listed in Table 1. TLS was closely monitored in C1 and 8/21 participants developed TLS when VEN was administered in C1; 0/35 when it was not. However, monitoring for TLS in C1 became less stringent when VEN was not administered. Treatment related Grade ≥3 toxicities occurred in 47/56 participants (83.9%) with serious adverse events in 31 of 56 (55.5%). Atypical infections were seen; there was one treatment related death on study due to cytomegalovirus (CMV) encephalitis as well as PJP pneumonia which occurred after induction C6. Enrollment was temporarily suspended and CMV monitoring was implemented with no further occurrences. Another participant receiving mO later developed BK virus nephropathy following mO C6 and now requires ongoing hemodialysis. Another was diagnosed with Respiratory Syncytial Virus pneumonia 30 days after C6 and later PJP pneumonia after C2 of mO. Common (incidence >10%) AEs during induction are listed in Table 2. 45 of 56 (80.4%) participants were able to receive all 6 cycles of OB-VEN. CR was seen in 41 of 56 participants (73.2%, 2 sided 95% Confidence Interval (CI) 59.7-84.2%) at the EOI. 30 participants (53.5%) went onto maintenance. With a median follow up of 20.9 months, estimated 2 year Overall Survival (OS) and Progression-Free Survival (PFS) (90% CI) is 94.4% (82.4-98.3%) and 85.8% (68.8-93.9%) respectively. Conclusions This Phase II study of OB-VEN in untreated HTB FL showed high CR rate and met its primary endpoint with early signs of prolonged PFS. Laboratory TLS was identified but it was unclear if attributed solely to VEN, as baseline laboratory TLS rate for OB is unknown. The rate of Grade ≥3 AE of 83.9% (compared to 69% for OB in GALLIUM, Hiddeman JCO 2018) and the observation of opportunistic infections including CMV encephalitis, PJP pneumonia and BK nephropathy, suggests the combination is highly immunosuppressive. Therefore, while the study met its primary outcome, the combination of OB-VEN at 800 mg for 10 days, plus mO, does not have an acceptable risk/benefit profile. Participants will continue to be followed for efficacy and safety during the maintenance phase. Figure 1 Figure 1. Disclosures Portell: Acerta/AstraZeneca: Research Funding; SeaGen: Research Funding; Pharmacyclics: Honoraria; Xencor: Research Funding; Aptitude Health: Honoraria; BeiGene: Honoraria, Research Funding; Abbvie: Research Funding; TG Therapeutics: Honoraria, Research Funding; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Morphosys: Honoraria; Targeted Oncology: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Nowakowski: MorphoSys: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Selvita: Consultancy; Ryvu Therapeutics: Consultancy; Kyte Pharma: Consultancy. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. OffLabel Disclosure: Venetoclax is not approved for follicular lymphoma or in combination with bendamustine and obinutuzumab

Phase II study of AT-101 to abrogate Bcl-2-mediated resistance to androgen-deprivation therapy (ADT) in patients (pts) with newly diagnosed androgen-dependent metastatic prostate cancer (ADMPC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 137-137
Author(s):  
M. N. Stein ◽  
I. Khan ◽  
M. Hussain ◽  
G. Liu ◽  
G. Wilding ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Metastatic Prostate Cancer ◽  
Phase Ii Study ◽  
Sensory Neuropathy ◽  
Clinical Results ◽  
Nodal Metastasis ◽  
Intention To Treat ◽  
Study Results

137 Background: Preclinical studies demonstrate that Bcl-2 is over-expressed in most pts with prostate cancer, causes drug resistance to ADT, and that modulation of Bcl-2 improves sensitivity of tumor cells. We are conducting a phase II study for men with ADMPC to test the hypothesis that AT-101, a small molecule Bcl-2 inhibitor, improves clinical results of pts initiating ADT for metastatic prostate cancer. Building on results from SWOG 9346 (Hussain JCO 2006) demonstrating that PSA nadir after 7 mo of ADT predicts survival, we are using a novel phase II trial design, in which the primary endpoint is the percentage of patients with PSA ≤ 0.2 ng/ml at 7 mo of ADT plus AT-101. Methods: Pts had ADMPC, PSA > 5.0 ng/ml within 12 wks prior to registration and no prior ADT for metastatic disease. ADT with LHRH agonist and bicalutamide started 6 wks prior to initiation of oral AT-101, 20 mg/day for 21 days of 28 day cycle. Pts received up to 8 cycles of ADT and AT-101. A total of 55 pts were enrolled (to obtain 48 evaluable pts) to in a two stage design with null hypothesis 48% versus alternative 68% with PSA ≤ 0.2 at 7 mo. With α = 0.1 and β = 0.9, > 27 pts meeting this endpoint are required to recommend further study. Results: 55 pts were enrolled, median age 61.5 y; Gleason score (GS) 6 (5%),GS 7 (30%), GS 8 (24%), and GS 9 (41%). 3 pts had visceral mets and the remaining pts had bone or nodal metastasis. 42 pts have discontinued (9 toxicity, 9 progression, 1 withdrew) or completed (n = 23) 7 mo of treatment. In intention to treat analysis, 11 of 42 pts (26%) met the primary endpoint 10, of 42 (23%) pts had PSA > 0.2 and < 4.0 ng/ml after 7 mo. Grade 1/2 toxicities (%) included fatigue (36/9), nausea (20/9), vomiting (13/7), anorexia (15/2), AST/ALT (25/5), hypercalcemia (9/0), constipation (13/3), dry skin (9/0), anemia (18/0), sensory neuropathy (7/7), vomiting (12/7), hyperglycemia (7/4). Grade 3 toxicities were sensory neuropathy 2 pts, GI obstruction 1 pt, syncope 1 pt. Conclusions: Although final study results are pending the analysis of pts currently on therapy, 26% of pts achieved an undetectable PSA at 7 mo in a population with aggressive disease (66% GS ≥ 8). No significant financial relationships to disclose.

L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7514-7514 ◽  
Author(s):  
Kami J. Maddocks ◽  
Eva González Barca ◽  
Wojciech Jurczak ◽  
Anna Marina Liberati ◽  
Johannes Duell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
International Prognostic Index ◽  
Single Agent ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Cell Of Origin

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.

A Phase II Trial of Combination Bortezomib (Velcade®) and Rituximab for Untreated “High Tumor Burden” Indolent Non-Hodgkin Lymphoma (NHL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2004-2004
Author(s):  
Kevin A. David ◽  
Mitchell R. Smith ◽  
Izidore S. Lossos ◽  
Eren Roubal ◽  
Jane N. Winter ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Induction Therapy ◽  
Phase Ii Trial ◽  
International Prognostic Index ◽  
Single Agent ◽  
Tumor Burden ◽  
Consolidation Therapy ◽  
Cycle Number ◽  
High Tumor Burden

Abstract Traditional therapy for patients with symptomatic and/or high-risk indolent NHL most commonly includes rituximab combined with multiagent cytotoxic chemotherapy. However some patients are not able to tolerate chemotherapy due to advanced age and/ or co-morbidities. Further, combination of novel, targeted agents (non-chemotherapeutic) have been infrequently tested in newly diagnosed indolent NHL patient populations. Overall response rate (ORR) with single-agent rituximab in prior data for untreated indolent NHL was 73% with a complete remission (CR) rate of 37% following maintenance therapy (JCO2002; 20: 4261), although a good portion of patients in that series had low tumor burden at study entry. We hypothesized that frontline bortezomib and rituximab therapy would be effective and well tolerated for untreated “high tumor burden” indolent NHL. We have conducted a Simon 2-stage phase II trial for untreated indolent NHL. All patients were required to have “high tumor burden” as defined by Groupe D’Etude des Lymphomes Folliculaires (GELF) criteria. Induction therapy consisted of 3 cycles: bortezomib given at 1.6 mg/m2 days 1, 8, 15, and 22 q35 days for all 3 cycles and rituximab at 375 mg/m2 x 4 weekly doses for cycle 1, then day 1 only for cycles 2 and 3. Abbreviated consolidation therapy was subsequently given with 1 dose of each drug q2 months x 8 months. Responses were assessed by computerized tomography (CT) according to Cheson criteria (JCO 1999). We report here the results of the first stage of this 2-stage trial. Twenty-two patients have enrolled, of whom 17 were in the 1st stage. There were 9 women and 8 men; median age was 63 years (range 46–78 years). 14 patients had follicular lymphoma (FL), 2 marginal zone lymphoma, and 1 small lymphocytic lymphoma. 13 of 17 patients had stage IV disease and 4 had stage III. The median Follicular Lymphoma International Prognostic Index (FLIPI) was 3 (range 1–4) and the median follow-up was 13 months (range 1–24 months). Responses according to cycle number are shown in Table 1. After only 1 cycle, the ORR was 29% (all partial remissions (PRs)) with 71% stable disease (SD). Following cycle 3, ORR was 59% (24% CR). From cycle 1 to 3, 4/5 PRs converted to CR, 6 SDs converted to PR, while 1 PR and 4 SDs progressed or were removed from the study at physician discretion. 8 of 12 eligible patients have completed consolidation therapy. Following consolidation, 1 PR converted to CR and 2 SDs converted to PR for an ORR of 71%. According to histology, the ORR among FL patients after consolidation therapy was 86% (CR 36%, PR 50%). Therapy was very well tolerated. Grade 3 toxicities seen were lymphopenia, partial small bowel obstruction, and fatigue (all in 1 patient); no grade 4 toxicities occurred. Furthermore, no cytopenias or neurotoxicity was seen. Accrual to the 2nd stage is being completed. In summary, we found in the 1st stage of this phase II trial that bortezomib/rituximab combination therapy for untreated high tumor burden indolent NHL is well tolerated and active. Response rates improved throughout therapy (i.e., from cycle 1 through consolidation), although the CR rate achieved was low compared with chemotherapy-based regimens. Chemotherapy-based therapy should be considered standard therapy for frontline “high tumor burden” indolent NHL, although non-chemotherapy options may be considered for patients not anticipated to tolerate intensive therapy. Furthermore, responses seen here with bortezomib/rituximab, in a uniform high tumor burden patient population, were similar to rituximab alone in lower tumor burden populations. Analysis of clinical trials/reports in indolent NHL should include critical assessment of patient selection and future trials in high tumor burden should incorporate novel therapies into rituximab-chemotherapy based regimens. Table 1. Response according to cycle/treatment. After Cycle 1 After Cycle 3* Following consolidation therapy** *Three patients had PD, while 2 patients were taken off study (without PD) at physician discretion. **Eight of 12 eligible patients have completed post-induction therapy. ORR 29% (5/17) 59% (10/17) 71% (12/17) CR 0% 24% (4/17) 30% (5/17) PR 29% (5/17) 35% (6/17) 41% (7/17) SD 71% (12/17) 12% (2/17) 0% PD/off trial 0% 29% (5/17) 29% (5/17)

A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2931-2931
Author(s):  
Beata Holkova ◽  
Ashraf Z. Badros ◽  
Robert Geller ◽  
Peter M. Voorhees ◽  
Adriana Zingone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Subcutaneous Tissue ◽  
Single Agent ◽  
Mitogen Activated Protein Kinase ◽  
Response Threshold ◽  
Clinical Activity

Abstract Abstract 2931 AZD6244 is a potent, selective, oral, non-ATP competitive small molecule inhibitor of the mitogen-activated protein kinase, MEK 1/2 that has shown significant pre-clinical activity in multiple myeloma (MM) cells, both in vitro and in vivo, as well as a favorable clinical profile. The present phase II study was designed to determine the response rate for AZD6244 in patients with relapsed or refractory MM. The study utilized a two-stage Simon design to allow for early termination if there was strong evidence of regimen inactivity. Eligible patients were restricted to those with MM who have had at least 2 prior regimens. AZD6244 capsules (75 mg) were administered orally twice daily continuously for 28 day cycles. Response was evaluated after 3 cycles. To date, 37 patients have been enrolled (13 in the 1st stage and 24 in the 2nd stage). One subject enrolled in the 1st stage was not treated. Gender enrollment was balanced (male/female 18/19). The median age of treated patients was 65 years [range 43–81]. ECOG performance scores ranged from 0–2. The median number of prior therapies was 5 [range 2–11]. The most common treatment-related adverse events (occurring in 10–50% of patients) were leukopenia, acneiform rash and other skin/subcutaneous tissue manifestations, fatigue, limb edema, increased aspartate aminotransferase (AST), neutropenia, nausea, facial edema, vomiting, thrombocytopenia, increased creatine phosphokinase, and diarrhea. The most common grade 3 and 4 toxicities (CTCAE v4) included fatigue, peripheral sensory neuropathy, increased AST, neutropenia, nausea, hypotension, thrombocytopenia, increased alanine aminotransferase, and diarrhea. Five deaths have occurred: 2 associated with sepsis, 1 associated with acute kidney injury, all deemed possibly related to AZD6244; and 2 due to disease progression after discontinuation of study treatment. Two objective partial responses have been reported, the first of which justified expansion of the study to the 2nd stage. Twelve patients have had a best response of stable disease, 11 patients have had progressive disease, 1 patient withdrew after cycle 1 (unrelated to toxicity) and did not have response assessed, 3 patients died before response was assessed, and 7 patients are too early to evaluate. Accrual is ongoing to determine if the response threshold in the 2nd stage can be met. Correlative studies are ongoing and are designed to identify potential mechanisms of response/resistance to AZD6244, and to determine the effect of AZD6244 on the bone marrow microenvironment. These include, among others, assessment of pre- and post-treatment expression of phospho-MEK 1/2 and -ERK 1/2, and total levels of Bim. Fifteen patients consented to correlative sampling of bone marrow, blood and/or urine. Results and sample analysis are pending. It is concluded that AZD6244 has modest activity as a single agent in relapsed or refractory MM. This trial also provides a foundation for successor studies employing the MEK 1/2 inhibitor AZD6244 in combination with other agents in patients with MM. Disclosures: Voorhees: Pfizer: Research Funding; Centocor Ortho Biotech: Research Funding; Celgene: Research Funding; MedImmune: Consultancy; Merck: Research Funding.

Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 901-901 ◽  
Author(s):  
Nathan H Fowler ◽  
Sattva S. Neelapu ◽  
Fredrick B Hagemeister ◽  
Peter McLaughlin ◽  
Larry W. Kwak ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Single Agent ◽  
Data Monitoring Committee ◽  
Study Entry ◽  
Molecular Response ◽  
Advanced Stage ◽  
Indolent Lymphoma ◽  
Grade 3

Abstract Abstract 901 Background: The optimal management of patients (pts) with untreated, advanced stage indolent non-Hodgkins lymphoma (NHL) is evolving. Although several traditional chemo-immunotherapy regimens achieve high overall response (OR) rates, toxicity is common and nearly all patients relapse. Lenalidomide has single-agent activity in relapsed indolent NHL, and rituximab is effective alone and in combination with chemotherapy in untreated pts. Preclinical studies suggest that lenalidomide may augment immune effector cell function and ADCC in the presence of rituximab. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, advanced stage, indolent NHL. Methods: Pts with advanced stage untreated indolent NHL and measurable disease (>1.5cm) were eligible for study entry. Pts received 20 mg/day of lenalidomide on days 1–21 and rituximab 375 mg/m2 on day 1 of each 28 day cycle for 6 cycles. Patients with evidence of tumor response could continue up to 12 cycles. To reduce the incidence of tumor flare, pts with small lymphocytic lymphoma (SLL) started at 10mg, with monthly dose escalation. Pts were evaluable for response if they had at least 1 response assessment. Prophylactic growth factors were not used. Response was assessed every 3 cycles using the 1999 International Working Group Response Criteria. Results: The study enrolled 110 pts; all have completed treatment or are off-study, and 103 pts are evaluable for response. Histologies included: SLL n=30, follicular lymphoma (FL) n=50, and marginal zone lymphoma (MZL) n=30. The median age was 58 (34-84) years, and 53% were male. Of the 46 evaluable pts with FL,78% had a FLIPI score of ≥ 2, and 52% met GELF criteria for high tumor burden. The best response for the 103 evaluable pts is listed in Table 1. Among the FL pts, responses were high regardless of FLIPI score, tumor bulk, or GELF criteria at study entry. At the completion of therapy nearly all FL pts demonstrated molecular response with the absence of detectable BCL-2 by PCR. Forty five evaluable pts with FL had a positive PET scan prior to therapy and 42 (93%) attained a complete metabolic response following treatment. At a median follow up of 22 months, the estimated 2 year progression free survival (PFS) is 83% for all pts and 89% in pts with FL. Among all pts, grade ≥3 neutropenia occurred in 40% (13% of total cycles) and thrombocytopenia occurred in 4% of pts. The most common grade ≥ 3 non-hematologic toxicities included rash (8 pts), muscle pain (7 pts), fatigue (3 pts), thrombosis (3 pts). Two episodes of neutropenic fever occurred. Six pts stopped treatment due to adverse events. Conclusion: The combination of lenalidomide and rituximab is active and tolerable in pts with untreated indolent lymphoma. High complete response rates with durable remissions were observed in patients with follicular lymphoma. Randomized studies comparing this regimen versus traditional combination chemotherapy regimens are underway. Disclosures: Fowler: Celgene: Research Funding; Roche: Research Funding. Off Label Use: lenalidomide. Neelapu:Celgene: Research Funding. McLaughlin:Celgene: Data Monitoring Committee for another study Other. Fanale:Celgene: Honoraria, Research Funding. Wang:Pharmacyclic: Research Funding. Lacerte:Celgene: Honoraria. Samaniego:Celgene: Research Funding.

scholarly journals A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up

2016 ◽  
Vol 137 (1) ◽  
pp. 7-14 ◽  
Author(s):  
Alessia Bari ◽  
Raffaella Marcheselli ◽  
Luigi Marcheselli ◽  
Isabel Alvarez ◽  
Samantha Pozzi ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Small Sample Size ◽  
Single Agent ◽  
Progression Free Survival ◽  
Small Sample ◽  
Additional Tool ◽  
Heavily Pretreated

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.

scholarly journals A Phase II Study Evaluating the Combination of Nivolumab (Nivo) or Ipilimumab (Ipi) with Azacitidine in Pts with Previously Treated or Untreated Myelodysplastic Syndromes (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 344-344 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Naval G. Daver ◽  
Guillermo Montalban-Bravo ◽  
Elias J. Jabbour ◽  
Courtney D. DiNardo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Single Agent ◽  
Stopping Rule ◽  
Stopping Rules ◽  
Clinical Activity ◽  
Previously Treated

Abstract INTRODUCTION: Outcomes of pts with MDS after hypomethylating agent (HMA) failure remain poor. Improving the response and survival of pts with higher-risk MDS and developing treatments for pts after HMA failure is needed. Upregulation of PD-1, PD-L1 and CTLA-4 in MDS CD34+ cells after exposure and loss of response to HMA have been reported (Yang, Leukemia 2014). Nivo and Ipi are monoclonal antibodies targeting PD-1 and CTLA-4, respectively, with clinical activity in solid tumors. We hypothesized that use of these drugs after HMA failure or in combination with azacitidine (AZA) in the frontline setting may improve treatment outcomes of pts with MDS. METHODS: We designed a phase II study of Nivo or Ipi in monotherapy or combination for pts with MDS. Pts with prior therapy with HMA were to be treated in one of 3 consecutive cohorts: cohort #1: Nivo 3mg/kg iv days 1 and 15 of a 28 day cycle; cohort #2: Ipi 3mg/kg iv on day 1 of a 21 day cycle; cohort #3: Nivo 3 mg/kg iv on days 1 and 15 + Ipi 3 mg/kg iv on day 1 of a 28 day cycle. The study design allowed for AZA add-back after 6 cycles of therapy if there was no response or progression. Pts with previously untreated MDS were to be treated in one of 3 consecutive cohorts combining AZA 75mg/m2 iv daily days 1-5 of a 28 day cycle in each cohort with: cohort #4: Nivo 3mg/kg iv Days 6 and 20; cohort #5: Ipi 3mg/kg iv on day 6; and cohort #6: Nivo 3 mg/kg iv on days 6 and 20 + Ipi 3 mg/kg iv on day 6. The maximum size per cohort is 20 pts. The primary endpoint is to determine the safety of Nivo or Ipi as single agents or in combination with AZA. Secondary objectives included overall response rate (ORR) and assessment of biological activity. Responses were evaluated following the revised 2006 International Working Group (IWG) criteria. The study included stopping rules for response and toxicity. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. RESULTS: A total of 39 pts were registered between September 2015 and July 2016, with 2 enrollment failures, 13 (35%) treated with frontline AZA+Nivo, and 15 (41%) and 9 (24%) with Nivo or Ipi after HMA failure, respectively. Thirty-five pts (95%) are evaluable for toxicity and 33 (89%) for response at the time of analysis. Patient characteristics are shown in Table 1. The median number of treatment cycles was 4 (range 2-11) in pts treated with AZA+Nivo, 3 (1-8) in the Nivo cohort, and 3 (2-4) in the Ipi cohort. A total of 25 (71%) pts experienced at least one AE during therapy (Table 2), with 3 (27%) pts in the AZA+Nivo cohort, 6 (40%) in the Nivo cohort, and 3 (33%) in the Ipi cohort having related grade ≥3 non-hematologic AEs. Therefore, the stopping rule for toxicity was not met in any of the cohorts. Delays of therapy due to AEs were required in 9 pts due to: rash (N=1), adrenal insufficiency (N=1), colitis (N=1), thyroiditis (N=2), pneumonitis (N=3), and nephritis (N=1). Early 8-week mortality occurred in 1 patient due to a non-related intracranial hemorrhage. The ORR was 69% (6/11) in the AZA+Nivo cohort including 2 CR, 5 mCR+HI, and 2 HI. The ORR was 0% and 22% (2/9) in the Nivo and Ipi arms, respectively (p=0.156). Therefore, the stopping rule for response was met on the Nivo arm, and enrollment after patient 15 was stopped. A total of 4 and 1 pts required addition of AZA due to lack of response on the Nivo and Ipi arms, respectively. At the present time of follow up, 18 (49%) pts remain on study, with 3 having been taken off study due to death (all in the Nivo arm), 3 due to no response (AZA+Nivo: 1; Nivo: 2), 6 due to progression to acute leukemia (AZA+Nivo: 1; Nivo: 4; Ipi: 1), 1 due to transplant, and 1 due to side effects from therapy in the Ipi arm. Immunophenotypic analysis of stem cell and progenitor compartments (Figure 1A) was performed in 27 pts, including PD-1 and PD-L1 expression analysis in 16 pts. Increased PD-1 and PD-L1 expression on progenitor and stem cell compartments was observed in 3 and 4 pts, respectively (Figure 1B). Treatment with PD-1 inhibitors could not overcome the aberrant differentiation patterns. No differences in response were observed based on PD-1 bone marrow expression. CONCLUSION: Preliminary results indicate that PD-1 blockade with Nivo in combination with AZA in untreated higher-risk MDS pts is associated with a tolerable safety profile and clinical activity. Single-agent Ipi is capable of inducing responses in previously treated MDS pts. Single-agent Nivo did not show clinical activity. Further follow-up is needed to update efficacy and safety data. Table 1. Table 1. Table 2. Table 2. Figure 1. Figure 1. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. DiNardo:Novartis: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

A Phase II Study of Lenalidomide for Previously Untreated Deletion (del) 5q Acute Myeloid Leukemia (AML) Patients Age 60 or Older Who Are Not Candidates for Remission Induction Chemotherapy (Southwest Oncology Group Study S0605)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 332-332
Author(s):  
Mikkael A. Sekeres ◽  
Holly Gundacker ◽  
Jeffrey Lancet ◽  
Anjali Advani ◽  
Stephen Petersdorf ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Phase Ii ◽  
Induction Therapy ◽  
Stable Disease ◽  
Research Funding ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
World Health ◽  
Remission Induction

Abstract Abstract 332 Background: Older patients (pts, ≥60 years [yrs]) with AML have a dismal prognosis; the majority are not treated with any type of chemotherapy. Many have antecedent myelodysplastic syndromes (MDS), and 20–30% harbor chromosome 5 abnormalities. Lenalidomide (LEN) yields hematologic responses in 67% of lower-risk MDS pts with the del(5q) cytogenetic lesion, and complete responses (CRs) in 20% of higher-risk del(5q) MDS pts, all with isolated lesions. This Phase II study explores the safety and efficacy of single agent LEN in previously untreated older pts with AML and the del(5q) abnormality. Method: Untreated older pts with AML defined by 2001 World Health Organization criteria (without t(15;17)) who harbored a del(5q) cytogenetic abnormality (alone or in combination with other abnormalities) and who declined or were felt to be poor candidates for intensive induction chemotherapy were eligible. Pts were treated with LEN 50mg daily for up to 28 days as induction therapy. Concomitant cytotoxic or growth factor therapies were not allowed. Pts achieving stable disease or better per day 28 bone marrow assessment received post-remission LEN 10mg daily for 21 days of a 28-day cycle until disease progression or unacceptable toxicities. Enrollment from October 2006 through June 2010 was in 2 stages: 20 pts were registered; if at least 1 CR/CRi was observed using International Working Group response criteria, another 20 pts were to be enrolled. The study was designed with a critical level of 4.7% (erroneously concluding the regimen warrants further study if the true response rate is 5% or less) and power of 92% (probability of concluding that a response rate of 20% warrants further study). Result: Of 41 patients enrolled, 4 were excluded (2 without AML, 1 without del(5q), and 1 died prior to receiving therapy), leaving 37 for toxicity and efficacy analyses. Median age was 74 yrs (range, 60–94), 21 (57%) were female, 33 (89%) white, and 19 (51%) had prior MDS. Median presenting white blood cell count was 2,600 mcl (range, 600–658,000), and 30 (81%) had a performance status of 1. Of the 37 evaluable pts, 29 had pretreatment cytogenetic studies evaluated centrally. Two pts displayed no demonstrable abnormalities (but had del(5q) by fluorescence in situ hybridization); 5 had isolated del (5q); and 22 (76%) had complex karyotypes (≥3 abnormalities). Seven patients were removed from protocol therapy due to toxicities (infection, renal, respiratory, gastrointestinal, and rash), and 4 deaths occurred that were at least possibly related to therapy: 2 respiratory, 1 cardiac, and 1 febrile neutropenia. Five additional patients had grade 4 non-hematologic toxicities: hypocalcemia (2), fatigue (2), infection (1). Fourteen pts (38%) completed protocol induction therapy. Four pts (11%) of the 37 evaluable pts achieved CR/CRi following induction therapy, all of whom had complex karyotypes; 3 of the 4 relapsed after 1, 2, and 4 months, and the 4th died 13 months after CR without a report of relapse. Thirteen (35%) pts had stable disease following induction therapy; 8 went on to protocol post-remission therapy. Thirty-three of the 37 pts have died and the median overall survival was 2 months (95% CI, 1 to 4 months). The follow-up time of the 4 survivors was between 6 and 23 months. Conclusion: LEN as a single agent has modest activity and expected toxicity in older del(5q) AML pts, particularly when compared to other single-agent molecularly-targeted approaches, such as FLT3 inhibitors. Future trials will combine LEN with cytoxic or hypomethylator therapies in older del(5q) AML pts. Disclosures: Sekeres: Celgene: Honoraria. Off Label Use: Lenalidomide in (del)5q AML. Lancet:Celgene: Research Funding. List:Celgene: Research Funding.

Randomized, Phase II Study of the Thrombospondin-1-Mimetic Angiogenesis Inhibitor ABT-510 in Patients With Advanced Soft Tissue Sarcoma

2008 ◽  
Vol 26 (34) ◽  
pp. 5583-5588 ◽  
Author(s):  
Laurence H. Baker ◽  
Eric K. Rowinsky ◽  
David Mendelson ◽  
Rod A. Humerickhouse ◽  
Raymond A. Knight ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Day Treatment ◽  
Single Agent ◽  
Objective Response ◽  
Angiogenesis Inhibitor ◽  
Progression Free Survival ◽  
Study Results

Purpose Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients. Patients and Methods Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety. Results Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies. Conclusion ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.

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