Treatment of Patients with Non-Hodgkin Lymphoma (NHL) with CD19/CD3 Bispecific Antibody Blinatumomab (MT103): Double-Step Dose Increase to Continuous Infusion of 60 μg/m2/d Is Tolerable and Highly Effective

Abstract Abstract 2880 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). We have previously reported that blinatumomab delivered as single agent to patients with relapsed NHL and B-precursor acute lymphoblastic leukemia by continuous intravenous (CIV) infusion over 4–8 weeks depleted peripheral B cells, expanded T effector cells, and resulted in clinical responses. In this phase I study 52 patients (41 males, 11 females) have been treated, 21 with FL, 21 with MCL and 10 with other subtypes of lymphoma (MZL, SLL, LPL, CLL). Patients have received a median of 3 prior regimens (range 1 to 12). Ninety percent of the patients had prior exposure to rituximab and 45% to fludarabine. Patients were treated at a dose range from 0.5 to 90 μg/m2/d. The most common adverse events (AEs) occurred early, were transient, reversible and did not require discontinuation of treatment. The most common clinical AEs regardless of causality were pyrexia (75%), headache (45%) and fatigue (37%). The most common laboratory abnormality AEs regardless of causality were lymphopenia (75%), leukopenia (57%), thrombocytopenia (39%), C-reactive protein increase (53%) and fibrin D dimer increase (37%). The medically most important AEs that resulted in permanent discontinuation were CNS events. Signs and symptoms observed included kinetic tremor, speech impairment, disorientation, apraxia and seizure. All CNS events were fully reversible without sequelae and no pathological findings by MRI imaging were reported. Out of the 52 patients treated, 9 had to discontinue treatment permanently in the first cycle due to these CNS events. At a dose of 90 μg/m2/d two DLTs were observed which were CNS events during the DLT period of the first 2 weeks of treatment. Therefore 60μg/m2/d is the currently recommended dose. A low B to T cell ratio (<1:8) determined by FACS analysis in peripheral blood was found to be a risk factor for CNS events. No CNS events requiring treatment discontinuation occurred in 32 out of 34 patients with a high B:T cell ratio (≥1:8) up to 60μg/m2/d. In the 18 patients with low B:T cell ratio, 7 had CNS events requiring treatment discontinuation. Patients with low B:T cell ratio were subsequently treated with an alternative dosing schedule in which reduced doses of either 5 and 15 μg/m2/d were sequentially administered for 1 week respectively followed by an increase to 60 μg/m2/d. First single-step dosing was applied. However, CNS events leading to treatment discontinuation were still observed. Therefore a double-step regimen was implemented; in the initial cohort of 3 patients with low B:T cell ratio there were no treatment discontinuations due to CNS events. Overall 18 patients with FL or MCL were treated with constant or step dosing regimens at or reaching 60 μg/m2/d dose level. Eight out of the 9 patients with constant dosing showed an objective response by Cheson criteria. All responders had a high B:T cell ratio. One patient with a low B:T cell ratio was discontinued due to a CNS AE. Six out of 9 patients with low B:T cell ratio enrolled for step dosing showed an objective response. One patient (single step dosing) discontinued treatment because of a CNS AE and 2 patients discontinued because of tumor progression. As of June 15th 2010, response duration ranged from 1 to 30+ months. Median for response duration was 26 months with 5 out of 14 responses ongoing. Table 1: Response evaluation in patients enrolled in 60 μg/m2/d cohorts. Dose Level Cohort Patients Complete Response Partial Response Overall Response FL MCL Total FL MCL Total FL MCL Total FL MCL Total 60 μg/m2/d Constant 6 3 9 2 1 3 4 1 5 6 2 8 5 or 15 then 60 μg/m2/d Single step 3 3 6 2 0 2 1 1 2 3 1 4 5/15/60 μg/m2/d Double Step 2 1 3 0 0 0 2 0 2 2 0 2 Total 11 7 18 4 1 5 7 2 9 11 3 14 These data confirm high single-agent activity of blinatumomab with long lasting remissions. Initial data with double step dosing demonstrate that this approach maintains clinical activity without discontinuations due to CNS AEs. Evaluation of safety and clinical efficacy of this uniform double step schedule including other subtypes of NHL is ongoing. Disclosure: Scheele: Micromet Inc.: Employment. Zugmaier:Micromet Inc.: Employment. Nagorsen:Micromet Inc.: Employment. Klinger:Micromet Inc.: Employment. Schmidt:Micromet Inc.: Employment. Klappers:Micromet. Inc: Employment. Kufer:Micromet Inc.: Employment. Bargou:Micromet Inc.: Consultancy.

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Sustained Response Duration Seen after Treatment with Single Agent Blinatumomab (MT103/MEDI-538) in the Ongoing Phase I Study MT103- 104 in Patients with Relapsed NHL

Blood ◽

10.1182/blood.v112.11.267.267 ◽

2008 ◽

Vol 112 (11) ◽

pp. 267-267 ◽

Cited By ~ 6

Author(s):

Ralf C Bargou ◽

Peter Kufer ◽

Mariele Goebeler ◽

Stefan Knop ◽

Hermann Einsele ◽

...

Keyword(s):

T Cell ◽

Dose Level ◽

Phase 1 ◽

Single Agent ◽

Cell Activity ◽

Response Duration ◽

Target Cells ◽

Dose Escalation Study ◽

Dose Levels ◽

Fatal Sepsis

Abstract Introduction: Blinatumomab (MT103/MEDI-538), a BiTE antibody targeting the CD19 antigen, is a member of a novel class of molecules that redirect T cells for lysis of target cells. A Phase 1 dose escalation study is being conducted in patients with advanced NHL. Methods: Relapsed NHL patients requiring treatment were included. Most patients were pre-treated, with a median of 3 previous chemo/immunotherapy regimens. To date, 7 dose levels ranging from 0.0005 to 0.09 mg/m2/24 h have been tested. Blinatumomab was continuously infused as single agent over a period of 4–8 weeks. Objective responses were assessed by Cheson criteria and centrally reviewed. Results: To date 39 patients have been treated. Most common adverse events (AEs) included lymphopenia, pyrexia, and leukopenia. The majority of AEs (>95%) improved or resolved during treatment. Permanent treatment discontinuation due to AEs occurred in a total of 8 patients, of which 6 had fully reversible CNS events. One patient with a history of nearly fatal sepsis, pre-existing hypogammaglobulinemia and bone marrow affection by chemotherapy, experienced a fatal sepsis 5 weeks after treatment start. Dose-dependent activity was observed in mantle cell lymphoma, follicular lymphoma and CLL with responses observed in 11 out of 27 patients treated at doses of 0.015 mg/m2/24 h and higher. Five of those patients had complete and six had partial responses. At the dose level of 0.060 mg/m2/24 h, 7 out of 7 patients have shown objective responses. Beside one relapse after 14 months, no treatment failure has so far been observed for responders at dose levels of 0.030 mg/m2/24 h and 0.060 mg/m2/24 h. Five patients at these dose levels have ongoing responses for more than 6 months. Interestingly, partial remissions converted into complete remissions in two patients four weeks after end of infusion suggesting either reduction in lesion size due to efflux of a previously expanded T cell pool or prolonged T cell activity. Conclusions: Blinatumomab as single agent induced apparently durable responses in pre-treated B-NHL patients with the highest response rate at a dose level of 0.06 mg/m2/24 h. Recruitment is ongoing.

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523 Preliminary clinical experience with XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.523 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A553-A553

Author(s):

Elaine Shum ◽

Matthew Reilley ◽

Yana Najjar ◽

Adil Daud ◽

John Thompson ◽

...

Keyword(s):

Prostate Cancer ◽

T Cell ◽

Solid Tumors ◽

Dose Escalation ◽

Bispecific Antibody ◽

Objective Response ◽

Checkpoint Blockade ◽

List Type ◽

Advanced Solid Tumors ◽

Tumor Types

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

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A Phase I Trial of Subcutaneous (SQ) Dose-Escalated Alemtuzumab in Patients with T-Cell Lymphoproliferative Disorders (T-LPD).

Blood ◽

10.1182/blood.v110.11.3417.3417 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3417-3417 ◽

Cited By ~ 1

Author(s):

Pierluigi Porcu ◽

Robert A. Baiocchi ◽

Thomas S. Lin ◽

Kristie A. Blum ◽

Patricia Curtis ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Dose Level ◽

Fungal Infections ◽

Single Agent ◽

Lymphoproliferative Disorders ◽

Hematologic Toxicity ◽

T Cell Clone ◽

Oral Valganciclovir ◽

Cmv Reactivation

Abstract BACKGROUND: T-cell lymphoproliferative disorders (T-LPD) are heterogeneous and highly chemoresistant malignancies without standard therapy. With few exceptions, cure rates with combination chemotherapy do not exceed 25–30%. We have shown that alemtuzumab (A), a humanized IgG1 targeting the CD52 antigen expressed on most human leukocytes, is cytotoxic for malignant T-cells in vitro and in vivo, regardless of p53 mutational status (Blood106: 3380–3382, 2005). We initiated a Phase I study with A and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in T-LPD. METHODS: Accrual goal: 18–21 pts with untreated (u) or relapsed (r)T-LPD, excluding untreated ALK-1-positive or primary cutaneous anaplastic large cell lymphoma. CD52 expression was not assessed. Other exclusion criteria: pregnancy, HIV+, HCV+, or HBV+. Primary objective: A maximal tolerated dose (MTD). DLT defined as grade (G) ≥ 3 (or non-reversible grade 2) non-hematologic toxicity or G4 neutropenia or thrombocytopenia requiring >7 day delays in therapy for > 3 times. All pts received single agent SQ A loading (3, 10, 30 mg) over 5 days followed by one SQ A dose with each cycle of CHOP every 21 days for a total of 8 cycles. A dose levels: 3, 10, 20, 30 mg. All pts received valacyclovir, trimethoprim-sulfamethoxasole prophylaxis and G-CSF. Erythropoietin was given according to published guidelines. RESULTS: 18 pts were enrolled (uPTCL=11, uT-PLL=2, rCTCL=3, uSezary Syndrome=2). Enrollment according to dose level: 3mg = 6 pts; 10mg = 3 pts; 20 mg = 6 pts; 30 mg = 3 pts. Median age: 62 years. All pts completed single agent SQ A loading on time with minimal local reactions. Ten pts completed all planned therapy. Six pts did not complete therapy: 2 rCTCL=stable disease, 1 uPTCL=poor compliance, 2 PTCL=pt witdrew, 1 uT-PLL=progression. Two pts (30 mg dose level) are receiving therapy. Toxicity: G4 febrile neutropenia=1; G3 fatigue=2, G3 anemia=2, G3 dyspnea=1, G3 emesis=2, G3 CMV infection=1. Cohort 1 was expanded due to asymptomatic CMV reactivation requiring hospitalization for thrice daily foscarnet. Subsequent asymptomatic CMV reactivations (N=4) were treated with oral valganciclovir until clearance. No symptomatic CMV reactivation or other viral or fungal infections were seen. Out of 107 cycles of A/CHOP given, only 3 had to be delayed. Four pts (1 PTCL, 1 T-PLL and 2 Sezary) are in continuous clinical and molecular (PCR) complete response at 36, 28, 18 and 12 months respectively. CONCLUSIONS: SQ A was safely administerd up to 20 mg with each cycle of CHOP chemotherapy and growth factor support without excessive myelosuppression or infectious AEs. Treatment at 30 mg dose level is in progress. Asymptomatic CMV reactivation can be managed with oral valganciclovir without discontinuation of therapy. Durable responses have been seen, including molecular clearance of the malignant T-cell clone.

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A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Cancers ◽

10.3390/cancers13164113 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4113

Author(s):

Fatih M. Uckun ◽

Tara L. Lin ◽

Alice S. Mims ◽

Prapti Patel ◽

Cynthia Lee ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Bispecific Antibody ◽

Single Agent ◽

Weekly Dose ◽

Independent Manner ◽

Phase 1B ◽

Acute Myeloid

APVO436 is a recombinant T cell-engaging humanized bispecific antibody designed to redirect host T cell cytotoxicity in an MHC-independent manner to CD123-expressing blast cells from patients with hematologic malignancies and has exhibited single-agent anti-leukemia activity in murine xenograft models of acute myeloid leukemia (AML). In this first-in-human (FIH) multicenter phase 1B study, we sought to determine the safety and tolerability of APVO436 in R/R AML/myelodysplastic syndrome (MDS) patients and identify a clinically active recommended phase 2 dose (RP2D) level for its further clinical development. A total of 46 R/R AML/MDS patients who had failed 1–8 prior lines of therapy received APVO436 as weekly intravenous (IV) infusions at 10 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.3 mcg to 60 mcg. APVO436 exhibited a favorable safety profile with acceptable tolerability and manageable drug-related adverse events (AEs), and its maximum tolerated dose (MTD) was not reached at a weekly dose of 60 mcg. The most common APVO436-related AEs were infusion-related reactions (IRR) occurring in 13 (28.3%) patients and cytokine release syndrome (CRS) occurring in 10 (21.7%). The single dose RP2D level was identified as 0.2 mcg/kg. Preliminary efficacy signals were observed in both AML and MDS patients: Prolonged stable disease (SD), partial remissions (PR), and complete remissions (CR) were observed in R/R AML patients as best overall responses to APVO436 at the RP2D level. Three of six evaluable MDS patients had marrow CRs. The safety and preliminary evidence of efficacy of APVO436 in R/R AML and MDS patients warrant further investigation of its clinical impact potential.

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A multi-center phase Ib/II study of nal-irinotecan, 5-fluouracil and leucovorin in combination with nivolumab as second-line therapy for patients with advanced unresectable biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps4154 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS4154-TPS4154

Author(s):

Vaibhav Sahai ◽

Tyler Howard Buckley ◽

Kent A. Griffith ◽

Mark Zalupski

Keyword(s):

Dose Level ◽

Biliary Tract ◽

Single Agent ◽

Objective Response ◽

Cell Subset ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Phase Ib ◽

Line Therapy

TPS4154 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy, and treatment beyond first-line platinum doublet remains investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells more sensitive to T cell-mediated lysis and neoantigen production, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent PD-1 antibody in BTC provide a rationale for combining chemotherapy and immunotherapy. This multi-center, phase Ib/II, single-arm study is designed to investigate the role of nal-irinotecan, 5-FU and leucovorin in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary carcinoma (intra- or extra-hepatic and gallbladder) with progression or intolerance of first-line systemic therapy (excluding irinotecan and PD-1/PD-L1 antibody), measurable disease per RECIST v1.1, ECOG PS 0-1, Child Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective of the phase Ib portion is to determine the recommended phase 2 dose, and of the phase II portion is to evaluate the median progression-free survival. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST, median OS and safety in this patient population. Exploratory objectives include identification of biomarker predictors of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis and immune cell subset analysis (tissue and blood). Therapy includes nal-irinotecan 70 mg/m2, leucovorin 200 (dose level -1) or 400 mg/m2 (dose level 0), 5-fluouracil 2400 mg/m2 IV over 46 hours, and nivolumab 240 mg on day 1 every 2 weeks for 6 months. In the absence of disease progression, pts may continue therapy for up to 2 years. Accrual goal is 30 evaluable pts. Using a null hypothesis value of median PFS of 2.9 months, and an alternative hypothesis of 5.0 months, this ongoing study has > 80% power, with a two-sided alpha of 0.05 to identify treatment efficacy of study arm. Clinical trial information: NCT03785873.

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Safety results from phase I/II study of the PI3Kβ inhibitor GSK2636771 (G) in combination with pembrolizumab (P) in patients (pts) with PD-1 refractory metastatic melanoma (MM) and PTEN loss.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e22000 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e22000-e22000 ◽

Cited By ~ 2

Author(s):

Hussein Abdul-Hassan Tawbi ◽

Weiyi Peng ◽

Suzanne Phillips ◽

Denai R. Milton ◽

Rodabe Navroze Amaria ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Dose Level ◽

Clinical Benefit ◽

Renal Toxicity ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Safety Data ◽

Pten Loss ◽

Higher Doses

e22000 Background: Checkpoint inhibitors (CPI) have improved survival and long-term disease control in 35-40% of pts with MM. Many pts derive no clinical benefit or progress after an initial response. Our group and others have shown that loss of the tumor suppressor protein PTEN occurs in multiple cancers, up to 30% of MM pts, activates the PI3K pathway, and correlates with decreased MM response rates to CPI and decreased T cell infiltrates. In PTEN-null MM preclinical models, inhibition of the PI3Kβ-subunit with GSK2636771 (G) was superior to pan-PI3K inhibitors, increased intratumoral T cell infiltration and the activity of CPI. To test our hypothesis that PI3Kβi reverses resistance to CPI, we are conducting a Phase I/II study (NCT03131908) combining G with P in PD-1 refractory pts with PTEN loss. Methods: The primary objective of Ph I portion is to determine the Maximum-Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) of G with P in PD-1 refractory pts (including melanoma, endometrial, TNBC, and prostate cancers) with PTEN loss. Pts receive P at 200mg IV q 3 wks. G starting dose level (DL1) was 300 mg PO qd for 21 days and escalated to 400 mg PO qd (DL2) using a 3+3 design. A dose level -1 (DL-1) (200 mg PO qd) was also included in the event of unacceptable toxicities at higher doses. Ph II will accrue 35 pts at the RP2D. This study is continuously monitored for toxicity and futility. The primary objectives of Ph II are safety, tolerability, and efficacy of the combination as defined by Objective Response Rate (ORR) by RECIST 1.1. Secondary Objectives include the PKs of G and PD effects in tumor tissue as measured by pathway inhibition and T cell trafficking into tumors. Results: 13 pts have been treated, 6 at the 300mg (DL1), 5 at 400mg (DL2), and 2 at 200 mg (DL-1). One DLT (grade 3 hypocalcemia) was observed at the 300mg dose. Two DLTs were observed in the 400mg cohort, one of which was AKI requiring dialysis and the other was a Gr 3 rash. Based on this experience and additional safety data from GSK regarding renal toxicity, DL-1 was declared RP2D at 200mg. 2 pts at the RP2D have passed the DLT evaluation period without toxicities. Conclusions: The combination of G and P is being explored at the RP2D of 200 mg. Renal toxicity precluded higher doses. No objective responses have been observed although 2 pts have experienced prolonged clinical benefit including a MM pt with 27% decrease in tumor burden. Through longitudinal biopsies, we aim to better understand the role PTEN loss plays when targeted in combination with CPI. Clinical trial information: NCT03131908.

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Phase I/II study of vorolanib plus nivolumab in patients with thoracic malignancies: immunotherapy (IO) correlatives to differentiate responders from nonresponders.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21019 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21019-e21019

Author(s):

Katy Beckermann ◽

Christine M. Bestvina ◽

Jennifer G. Whisenant ◽

Hossein Borghaei ◽

Taofeek Kunle Owonikoko ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

T Cell Activation ◽

Stable Disease ◽

Single Agent ◽

Objective Response ◽

Acquired Resistance ◽

Response To Therapy ◽

Activation Markers ◽

Nsclc Patients

e21019 Background: VEGF inhibition is suggested to enhance innate T cell function, activate dendritic cells, block recruitment of regulatory T cells, and decrease myeloid-derived suppressor cells. Vorolanib is a tyrosine kinase inhibitor that is structurally similar to sunitinib but designed to improve safety without compromising efficacy. Response to checkpoint inhibitors in patients with thoracic tumors is limited, thus we designed this multi-institutional, phase I/II study (NCT03583086) to explore safety and efficacy of combining vorolanib and nivolumab. Here we present updated results in the NSCLC, thymic, and SCLC cohorts, including patients previously treated with single agent IO. Methods: The Phase I maximum tolerated dose was 200 mg vorolanib and 240 mg nivolumab q2w. Phase II is ongoing and uses a two-stage MinMax design to assess the objective response rate (RR) in SCLC, thymic carcinoma, and three NSCLC cohorts: 1) IO naïve; 2) primary refractory, defined as radiographic progression < 12 weeks of starting IO; and 3) acquired resistance, defined as achieving at least stable disease ≥12 weeks to IO followed by progression. Results: As of December 2019, 37 patients had enrolled, 38% female, 11% never smokers, median age 66. The disease control rate (DCR) across all cohorts is 65% (20/31 evaluable patients) and the RR is 13% (4/31). In the NSCLC cohort, the overall RR is 14% (3/21); the RR is 33% (2/6) in IO naïve patients, including 2 on therapy > 17 months. RR in the NSCLC patients with acquired resistance is 14% (1/7) with an 86% (6/7) DCR. No responses in the primary refractory cohort but the DCR is 50% (4/8). DCR in the SCLC and thymic cohorts is 40% (2/5) and 50% (2/4), respectively; 1 thymic patient had a partial response with a complete response in target lesions. Exploratory correlatives, including mass cytometry analysis and single cell gene expression, are being performed in order to understand changes in macrophages and T cell activation markers to differentiate the underlying biology of the tumor and the microenvironment between responders and nonresponders. Conclusions: The addition of vorolanib nearly doubled the RR in the IO naïve NSCLC patients compared to historical data with single agent nivolumab. Additionally, 67% of NSCLC patients with prior IO achieved at least stable disease, 1 patient with acquired resistance had a response. Correlatives that may help define biomarkers of response to therapy will be presented among different cohorts of patients. Clinical trial information: NCT03583086 .

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A Multi-Center Phase II Study (SAKK 36/06) of Single Agent Everolimus (RAD001) In Patients with Relapsed or Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v116.21.2803.2803 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2803-2803 ◽

Cited By ~ 1

Author(s):

Christoph Renner ◽

Pier Luigi Zinzani ◽

Remy Gressin ◽

Dirk Klingbiel ◽

Laurence Favet ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

Objective Response ◽

Response Duration ◽

Molecular Response ◽

Hematopoietic Stem ◽

Mantle Cell

Abstract Abstract 2803 Introduction: Mantle cell lymphoma (MCL) accounts for 6% of all B-cell lymphomas and remains incurable for most patients. Those who relapse after first line therapy or hematopoietic stem cell transplantation have a dismal prognosis with short response duration after salvage therapy. On a molecular level, MCL is characterised by the translocation t[11;14] leading to Cyclin D1 overexpression. Cyclin D1 is downstream of the mammalian target of rapamycin (mTOR) kinase and can be effectively blocked by mTOR inhibitors such as temsirolimus. We set out to define the single agent activity of the orally available mTOR inhibitor everolimus (RAD001) in a prospective, multi-centre trial in patients with relapsed or refractory MCL (NCT00516412). The study was performed in collaboration with the EU-MCL network. Methods: Eligible patients with histologically/cytologically confirmed relapsed (not more than 3 prior lines of systemic treatment) or refractory MCL received everolimus 10 mg orally daily on day 1 – 28 of each cycle (4 weeks) for 6 cycles or until disease progression. The primary endpoint was the best objective response with adverse reactions, time to progression (TTP), time to treatment failure, response duration and molecular response as secondary endpoints. A response rate of ≤ 10% was considered uninteresting and, conversely, promising if ≥ 30%. The required sample size was 35 pts using the Simon's optimal two-stage design with 90% power and 5% significance. Results: A total of 36 patients with 35 evaluable patients from 19 centers were enrolled between August 2007 and January 2010. The median age was 69.4 years (range 40.1 to 84.9 years), with 22 males and 13 females. Thirty patients presented with relapsed and 5 with refractory MCL with a median of two prior therapies. Treatment was generally well tolerated with anemia (11%), thrombocytopenia (11%), neutropenia (8%), diarrhea (3%) and fatigue (3%) being the most frequent complications of CTC grade III or higher. Eighteen patients received 6 or more cycles of everolimus treatment. The objective response rate was 20% (95% CI: 8–37%) with 2 CR, 5 PR, 17 SD, and 11 PD. At a median follow-up of 6 months, TTP was 5.45 months (95% CI: 2.8–8.2 months) for the entire population and 10.6 months for the 18 patients receiving 6 or more cycles of treatment. Conclusion: This study demonstrates that single agent everolimus 10 mg once daily orally is well tolerated. The null hypothesis of inactivity could be rejected indicating a moderate anti-lymphoma activity in relapsed/refractory MCL. Further studies of either everolimus in combination with chemotherapy or as single agent for maintenance treatment are warranted in MCL. Disclosures: Off Label Use: everolimus for the treatment of mantle cell lymphoma.

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Updated Results of a Phase I Study of Flavopiridol in Acute Leukemias Using a Novel, Pharmacokinetically Derived Schedule: Clinical Activity Including Hyperacute Tumor Lysis Syndrome (TLS), Pharmacokinetics (PK), and Pharmacodynamics (PD).

Blood ◽

10.1182/blood.v108.11.4578.4578 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4578-4578

Author(s):

William Blum ◽

Rebecca B. Klisovic ◽

Cheryl Kefauver ◽

Amy Johnson ◽

Mitch Phelps ◽

...

Keyword(s):

Bone Marrow ◽

Acute Leukemia ◽

Phase I ◽

Dose Level ◽

Dose Escalation ◽

Single Agent ◽

Objective Response ◽

Tumor Lysis Syndrome ◽

Acute Leukemias ◽

Tumor Lysis

Abstract Flavopiridol is a cyclin-dependent kinase inhibitor that induces apoptosis in acute leukemia cell lines. In earlier studies with flavopiridol in several malignancies, plasma concentrations of flavopiridol were not reached or maintained at sufficient levels to induce apoptosis due to unexpectedly high levels of bound drug in human serum relative to fetal calf serum used in preclinical studies. PK modeling in chronic lymphocytic leukemia (CLL) cells cultured in human plasma in vitro indicated that administering flavopiridol by 30 minute intravenous (IV) bolus followed by 4 hour continuous IV infusion (CIVI) would achieve sustained in vivo plasma drug concentration and time exposure similar to that necessary to induce apoptosis. We designed a phase I dose escalation trial in acute leukemias of single agent flavopiridol given as a 30 minute bolus followed by a 4 hour CIVI on days 1–3 with the ability to repeat cycles every 21 days; 16 patients (pts) have been enrolled to date. Dose escalation was as follows (bolus dose/4 hr CIVI dose in mg/m2): 20/30 (n=3), 30/35 (n=7), 30/50 (n=3), and 40/60 (n=3). Based on prior experience with flavopiridol at our institution in CLL, aggressive measures for the prevention and management of hyperacute tumor lysis syndrome (TLS) were employed. Pts had relapsed/refractory AML (N=12) and ALL (N=4), and were 25–78 yrs old (median age 64 yrs). Average plasma levels were 1.0–2.5 μM at the first three dose levels during the infusion (N=13) and declined with terminal half-lives comparable to previously reported 72 hr and more recent 4.5 hr infusions. Clinically significant TLS occurred in 2/16 pts with chemical evidence of lysis in 4 additional pts. A dose-limiting toxicity (renal failure) occurred at dose level 4 (40 mg/m2 bolus/60 mg/m2 CIVI), and the level is currently being expanded. Treatment was otherwise well tolerated. Downregulation of Mcl-1 protein by standard immunoblotting at 4 and/or 24 hrs was demonstrated in blood and/or bone marrow cells of 6/10 patients Anti-leukemic activity including transient reductions in WBCs/circulating blasts (n=7), bone marrow blasts (n=2), and platelet transfusion independence (n=1) was observed. Two received a second course of therapy, but no pt experienced an objective response by standard criteria. The current dose level exceeds that previously given in ongoing CLL studies; dose escalation to identify the maximum tolerated dose using this pharmacokinetically derived schedule in acute leukemia continues. Given the activity of this drug as a single agent, combination studies with conventional chemotherapy or other novel agents in acute leukemias should be considered.

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