Tazemetostat (TAZ) in relapsed/refractory (R/R) follicular lymphoma (FL): Propensity-score matched analysis of E7438-G000-101 trial outcomes.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18627-e18627
Author(s):  
David Proudman ◽  
Deepshekhar Gupta ◽  
Dave Nellesen ◽  
Alex Wong ◽  
Jay Yang ◽  
...  
Keyword(s):  
Propensity Score ◽  
Single Agent ◽  
Objective Response ◽  
Prior History ◽  
Cell Transplant ◽  
Phase 2 ◽  
Matched Sample ◽  
Hematopoietic Stem ◽  
Disease Characteristics ◽  
Baseline Characteristics

e18627 Background: Oncology drug development often requires the use of non-randomized, open-label, phase 2 basket studies to better understand the early activity and safety of a potential new therapy. As such, baseline demographics and disease characteristics may differ between cohorts which can impact the perception of efficacy between cohorts. TAZ, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was approved by the US FDA after demonstrating single-agent, antitumor activity in a phase 2 study in adults with wild-type (WT) or mutant (MT) EZH2 R/R FL who had received ≥2 prior systemic therapies (NCT01897571). Differences between the cohorts in baseline characteristics known to be prognostic for clinical outcomes were noted, with the WT EZH2 cohort enrolling more patients with poor-risk features. This analysis assessed outcomes in the 2 groups after minimizing differences in baseline characteristics by creating a matched sample of directly comparable WT and MT patients. Methods: Propensity scores for each WT (n = 54) and MT (n = 45) EZH2 patient in the study were generated, based on the likelihood of being selected given their baseline characteristics. Characteristics identified for inclusion in the model were chosen if they were prognostic based on peer-reviewed literature and where larger differences were observed between cohorts at baseline: ECOG performance status, number of prior lines of anticancer therapy, progression of disease within 24 months, double refractory status, and prior history of hematopoietic stem cell transplant. Patients were matched 1:1 on propensity score, using a nearest-neighbor approach with caliper restrictions. Baseline covariates between the two matched groups were found to be sufficiently balanced. Objective response rate (ORR) point estimates were measured for the matched WT and MT EZH2 groups, and progression-free survival (PFS) was described using Kaplan-Meier analyses. Results: The propensity-matched sample included 56 patients (28 WT and 28 MT). Prior to matching, ORR was 35% (95% CI [22%, 48%]) in the WT and 69% (95% CI [55%, 83%]) in MT EZH2 groups; after matching, the ORR was 50% (95% CI [31%, 69%]) and 71% (95% CI [54%, 88%]), respectively. Median PFS was 11.1 months (95% CI [5.4, 16.7]) in the WT and 13.8 months (95% CI [11.1, 22.1]) in the MT EZH2 groups prior to matching, and 14.3 months (95% CI [11.1, inf]) and 14.8 (95% CI [10.7, inf]) months in the WT and MT EZH2 matched groups, respectively. Conclusions: As expected, efficacy remained higher in the MT EZH2 group; however, after adjustment, the ORR and PFS improved in the WT EZH2 group. This hypothesis-generating analysis suggests that outcomes in patients with WT EZH2 R/R FL treated with TAZ may have been more similar to those in the MT EZH2 group in the phase 2 trial had the baseline disease characteristics been more equally matched.

scholarly journals Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial

2020 ◽  
Vol 8 (1) ◽  
pp. e000798
Author(s):  
Lu Xie ◽  
Jie Xu ◽  
Xin Sun ◽  
Wei Guo ◽  
Jin Gu ◽  
...  
Keyword(s):  
Pulmonary Metastases ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase ◽  
High Grade Osteosarcoma

BackgroundResults of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.MethodsThis open-label, phase 2 trial was conducted at Peking University People’s Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.Results43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.ConclusionsAlthough the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.Trial registration numberNCT03359018.

Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4528-4528
Author(s):  
Richard Sposto ◽  
Elizabeth A. Raetz ◽  
Charles P. Reynolds ◽  
Paul S. Gaynon
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Phase I Trials ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a > 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia. Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity. Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time. Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.

Tanespimycin (T) + Bortezomib (BZ) in Multiple Myeloma (MM): Confirmation of the Recommended Dose Using a Novel Formulation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1165-1165 ◽  
Author(s):  
Paul G. Richardson ◽  
Asher Chanan-Khan ◽  
Sagar Lonial ◽  
Amrita Krishman ◽  
Michael Carroll ◽  
...  
Keyword(s):  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Durable Response ◽  
Cd8 Cells ◽  
Suspension Formulation ◽  
Client Proteins ◽  
M Spike ◽  
Dose Levels

Abstract Introduction: Tanespimycin (17-AAG/KOS-953) disrupts Hsp90, a molecular chaperone of client proteins including IL-6 and IGF-1R, key to MM growth, survival and drug resistance. Single agent T is well tolerated with modest anti-MM activity in Phase 1; preclinical studies suggest synergy with BZ. Methods: To date, 63 patients (pts) received BZ followed by 1-hr infusion of T on D1,4,8,11 q 21d. Dose escalating phase: 36 pts were enrolled in 7 cohorts (T 100–340 mg/m2; BZ 0.7–1.3 mg/m2). Confirmation of the phase 2 dose occurred in 27 pts across 2 groups: 1 group received a Cremophor formulation; a 2nd group received a suspension formulation without steroid premedication (n=13 and 14 pts, respectively). Results: The recommended phase 2 dose equals T 340 / BZ 1.3 mg/m2. At this dose (n=26), common all-grade (G) drug-related toxicity in pts included diarrhea (39%), dizziness (27%), nausea (23%), AST (23%), vomiting (23%), fatigue, ALT and peripheral edema (all 19%). No difference in toxicity was seen between the 2 formulations, consistent with the clinical experience to date using the suspension product (n=31). G3 and G4 thrombocytopenia was noted in 15% and 12%; no other G3 toxicity was observed in more than 1 pt. No G3 neurotoxicity was seen at any dose. For the Cremophor (n=18) and suspension formulation (n=12), AUC (parent+metabolite) equaled 30.1 ± 11.1 and 30.6 ± 15.6 ug/mL*h. PK of T was similar with/without BZ (total AUC: 30.7 ± 14.8 vs. 28.9 ± 10.5). Inhibition of 20S proteasome with T+BZ was similar to BZ single-agent. PBLs maintained induction of Hsp70 throughout the 3–4 day dosing interval; D11 (pre-infusion at 340 mg/m2) showed similar Hsp70 induction for the Cremophor and suspension formulations. Myeloma CD138 cells but not CD4 or CD8 cells from serial BM aspirates showed induction of apoptosis by flow cytometry. Responses were seen across dose levels in BZ-naïve, pre-treated and refractory pts (defined as “no response to or disease progression within 60d of last dose of BZ-containing regimen”). Three BZ-refractory pts achieved a durable response: 1 pt with 3 prior regimens with confirmed PR after 2 cycles, continuing 18+ months on study (M-spike ↓92%); a 2nd pt with 2 prior regimens achieved PR after 2 cycles and continues 14+ months on study; a 3rd pt with 7 prior regimens with confirmed PR withdrew after 8 cycles with 12-month duration of PR. The incidence of objective response in pts receiving the Cremophor and suspension formulations was similar. To date, in the 5 BZ-naive pts evaluable for efficacy treated with the suspension, 4 pts achieved a confirmed response (1 CR, 2 PR and 1 MR); for Cremophor product, 8 out of 14 BZ-naive pts had a confirmed response (2CR, 2 PR and 4 MR). Conclusions: Treatment with T/BZ combination produces durable anti-MM activity in BZ-refractory pts. In BZ-naive pts, both formulations demonstrate substantial activity. The combination has very manageable toxicity without G3 neurotoxicity to date. Data support the use of the suspension formulation in myeloma trials. Phase 2/3 registrational program of T/BZ in relapsed MM is underway.

5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) As Therapy for Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 823-823 ◽  
Author(s):  
Naval Daver ◽  
Guillermo Garcia-Manero ◽  
Jorge E. Cortes ◽  
Lingsha Zhou ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
Single Agent ◽  
Myeloproliferative Neoplasm ◽  
Hematological Toxicity ◽  
Cell Transplant ◽  
Bone Marrow Biopsies ◽  
Baseline Characteristics ◽  
Grade 3

Abstract Background: Clinical trials exclusively focusing on pts with MDS/MPN are lacking. AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for primary myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs. Aim: To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)(ClinicalTrials.gov Identifier: NCT01787487). Methods: A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts. Results: 24 pts were enrolled between March 1, 2013 and April 1, 2015. Baseline characteristics are summarized in table 1. 17 pts remain alive after a median (med) follow-up of 6.0 (3.7 - 21.3+) months. Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). Responses were noted in 12 (50%) pts. Details of responses are shown in table 2. Med time to responses was 1.8 mos (0.7 - 5.5+) and the med duration of response is 7.0 mos (1.8 - 17.6+). Additionally, 9 pts had >5% pretreatment BM blasts: 6 of these pts had follow-up BM evaluations and 3 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (5.5 - 11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 3 of 11 (27%) evaluable pts after a med of 5.5 mos (2.1 - 5.6+) on therapy. The reduction was by one grade in all 3 pts (MF-2 to MF-1 in 2 pts, MF-1 to MF-0 in 1 pt) and was confirmed on a subsequent BM biopsy in 2 pts. No pts experienced grade 3/4 non-hematological toxicity. New onset grade 3/4 anemia and thrombocytopenia were seen in 12 (50%; of which 5 had a 2+ grade change) and 8 (31%) pts, respectively. The med overall survival is 15.1+ mos. 7 pts have died: pneumonia (n=3), sepsis (n=2), progression to AML (n=1), and transition to hospice (n=1). The AZA was started in cycle 4 in 12 pts (50%). The AZA was started earlier due to leukocytosis or increased blasts in 11 pts (46%), in cycle 1 (n=6), cycle 2 (n=4), and cycle 3 (n=1). 13 pts have discontinued protocol therapy due to leukocytosis (n=6), progression to AML (n=1), lack of response (n=3), pneumothorax (n=1), stem cell transplant (n=1), and loss of insurance (n=1), respectively. Conclusion: Concomitant administration of RUX with AZA was feasible and effective in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. This combination warrants further evaluation. Table 1. Baseline characteristics (N = 24) Characteristic N (%) / [range] Med age, years 71 [55 - 79] Prior treatment 9 (38) Diagnosis MDS/MPN-U CMML aCML 11 (46) 10 (42) 3 (12) MF - DIPSS Int-1/ Int-2/ High 4(17)/ 11(46) / 9(37) MDS - IPSS Low/ Int-1/ Int-2/ High 9(38) /12(50) / 2(8) / 1(4) Splenomegaly 12 (50) Med WBC x 109/L 26.3 [3 - 123.2] Peripheral blood blasts >/= 1% 17 (71%) LDH 1040 [409 - 3567] EUMNET fibrosis grade MF-1/ MF-2/ MF-3 10(42)/ 6(26)/ 1(4) JAK2 + 6 (25) Med JAK2 allele burden 42.2 [3 - 90] Karyotype Diploid Abnormal 18 (75) 6 (25) 28-gene molecular panel in 23 pts*, (1 pt not done) ASXL1 DNMT3A TET2 KRAS/NRAS PTPN11 IDH 2 4 (17) 4 (17) 3 (13) 2(8) / 2(8) 2(8) 2 (8) *Mutations identified in only 1 pt included EZH2, GATA2, RUNX1, MPL, KIT. Table 2. Response evaluation by the MDS/MPN IWG 2015 criteria Response category Evaluable pts Responders/Evaluable (%) *All responses, some pts have > 1 response All 12/24 (50) Clinical improvement (CI) spleen Pts with palpable spleen > 5 cm 8/11 (73) CI total symptom score Pts with baseline TSS > 20 3/12 (25) CI Hemoglobin (HGB) Baseline HGB < 10 g/dL 1/7 (15) CI Transfusion independence History of transfusion dependence 1/5 (20) Partial marrow response Baseline and follow-up BMs 5/11 (45) Optimal marrow response Baseline and follow-up BMs 1/11 (9) *No CR or PR documented Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8000-8000 ◽  
Author(s):  
A. Younes ◽  
M. Fanale ◽  
B. Pro ◽  
P. McLaughlin ◽  
S. Neelapu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Hdac Inhibitors ◽  
Response Analysis ◽  
Transcriptional Level ◽  
Cell Transplant ◽  
Tumor Reduction ◽  
Refractory Hodgkin Lymphoma

8000 Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (>20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (>1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial. No significant financial relationships to disclose.

Phase III study of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as front-line treatment for advanced classical Hodgkin lymphoma (HL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8612-TPS8612 ◽  
Author(s):  
Anas Younes ◽  
John Radford ◽  
Stephen Maxted Ansell ◽  
Andrea Gallamini ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
Pulmonary Toxicity ◽  
Prognostic Score ◽  
Single Agent ◽  
Objective Response ◽  
Brentuximab Vedotin ◽  
Phase Iii ◽  
Stage Iii ◽  
Cell Transplant ◽  
Line Treatment ◽  
Front Line

TPS8612 Background: Brentuximab vedotin, a CD30-targeted antibody-drug conjugate, has conditional approval in Europe for relapsed/refractory (RR) CD30-positive HL following autologous stem cell transplant (ASCT) or following ≥2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. ABVD, a common front-line regimen for advanced HL, achieves complete response (CR) rates of 70–80%. However, 10–20% of patients (pts) are refractory to front-line treatment and up to 35% relapse after front-line multi-modality therapy. In pts with relapsed HL post-ASCT, single-agent brentuximab vedotin yields an objective response rate of 75% (CR, 33%; Chen ASH 2012). In a phase 1 study in treatment-naïve HL pts, A+AVD was associated with manageable toxicity and a CR rate of 96%; brentuximab vedotin + ABVD was contraindicated due to pulmonary toxicity (Ansell ASH 2012). We hypothesized that substituting bleomycin with brentuximab vedotin would eliminate bleomycin-associated pulmonary toxicity and improve progression-free survival (PFS) compared to a standard ABVD regimen. Methods: This ongoing, open-label, randomized, multicenter study (NCT01712490) will compare A+AVD vs ABVD in 1040 pts with stage III/IV classical HL. Primary endpoint: modified (m) PFS (death, progression, and receipt of chemotherapy or radiotherapy by pts not in CR after completing A+AVD or ABVD will count as progression event). Key secondary endpoint: overall survival. Key inclusion criteria: histologically-confirmed previously untreated stage III/IV classical HL. Pts will be stratified by region and International Prognostic Score, and will be randomized 1:1 to receive A+AVD (brentuximab vedotin 1.2 mg/kg with each dose of AVD) or ABVD administered intravenously on Days 1 and 15 of 28-day cycles, for up to 6 cycles. Disease status and survival will be evaluated regularly until study closure. Safety assessments: incidence and severity of adverse events, changes to physical and laboratory tests. Clinical trial information: NCT01712490.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

Phase I/II study of R-ICE (rituximab-ifosfamide-carboplatin-etoposide) with lenalidomide (R2-ICE) in patients with first-relapse/primary refractory diffuse large B-cell lymphoma (DLBCL) in academic and community cancer research united (ACCRU) network.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8073-TPS8073 ◽  
Author(s):  
Francis Guerra-Bauman ◽  
Betsy LaPlant ◽  
William R. Macon ◽  
Thomas E. Witzig ◽  
Umar Farooq ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Phase 2 ◽  
Overall Response ◽  
Lymphoma Therapy

TPS8073 Background: Response rates to salvage immunochemotherapy in patients with DLBCL relapsing after or refractory (R/R DLBCL) to front line therapy remain unsatisfactory. Lenalidomide (Len) has significant single agent activity in relapsed/refractory DLBCL. The addition of lenalidomide (Len) days 1-7 to rituximab plus ifosfamide-carboplatin-etoposide (RICE) was shown to be feasible with promising efficacy in phase 1b study (Feldman T, et al. BJH, 2014). We developed phase I/II study to evaluate the safety and efficacy of the addition of Len (extended to 14 day schedule) to RICE (R2-ICE) for R/R-DLBCL patients who are candidates for stem cell transplant. Methods: The phase I portion was designed to determine the maximally tolerated dose Len in combination with RICE using the standard cohort 3+3 design. The escalation dose levels were 15 mg and 20 mg daily x 14 days. Prophylactic aspirin and growth factor support is mandatory. After 2 cycles of therapy response is evaluated with a PET/CT scan; the responding patients are eligible for 1-2 additional cycles of R2ICE as a bridging before HDC/SCT. The estimated overall response rate for two cycles of R-ICE in R/R DLBCL to RCHOP was estimated to be approximate 45%. We hypothesize that the addition of lenalidomide in the relapse setting could increase the overall response rate by approximately 20%. The one-stage design with an interim analysis being utilized in phase 2 requires 45 evaluable patients (one sided alpha = 0.09, power 90%). For Phase I, all types of B-cell lymphomas were eligible. For phase II portion only DLBCL patients are eligible per central pathology review. Other eligibility criteria include: received one line of previous anti-lymphoma therapy, ≥ 2 weeks from completion of prior anti-lymphoma therapy, candidate for HDC and SCT, adequate organ (creatinine clearance ≥ 60ml/min by Cockcroft-, total bilirubin ≤ 2 × ULN) and bone marrow function (ANC) ≥1500/mm3; platelet count ≥75,000/mm3). The use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed. 9 patients cleared phase 1 without DLT and dose of 20 mg days 1 -14 was recommend for phase 2 part (RP2D) of the study. The phase 2 study passed interim futility analysis and accrual continues. Correlatives include cell of origin by Nanostring, Myc/bcl2 expression and by FISH and minimal residual disease. PET scans are centrally reviewed including metabolic tumor volume. Clinical trial information: NCT02628405 .

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