Phase I Dose Escalation Study of Flavopiridol in Combination with Fludarabine and Rituximab: Activity in Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2492-2492
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Mollie E. Moran ◽  
David M. Lucas ◽  
Roshini S. Shank ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Mantle Cell ◽  
Grade 3

Abstract The cyclin-dependent kinase inhibitor flavopiridol was inactive when administered as a 72-hour infusion, but a 1-hr IV bolus dosing schedule demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis via a p53-independent mechanism. Thus, we hypothesized that flavopiridol may eliminate tumor cells resistant to fludarabine and rituximab. We report preliminary results of an ongoing phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab in patients (pts) with MCL, CLL and other indolent B-cell lymphoproliferative disorders. Pts had adequate marrow function (ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000), organ function, and performance status (ECOG 0–2) and provided informed consent. Pts in all cohorts received fludarabine 25 mg/m2 IV on days 1–5 and rituximab 375 mg/m2 on day 1 of each 28-day cycle. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), days 1–2 (cohort 2), or days 1–3 (cohort 3) of each cycle. Treatment was for up to 6 cycles, and pts were placed on prophylactic Bactrim and Valtrex. Fifteen pts have been enrolled to date, and 9 pts are evaluable for toxicity and response. Median age of these 9 pts was 67 years (range, 43–72), and 4 pts were male. Pts had the following diagnoses: CLL (5), MCL (2) and follicular lymphoma (FL; 2). Four pts had received 1–2 prior therapies; 5 pts were previously untreated. CLL pts had Rai stage III/IV disease (2) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. MCL/FL pts were stage III/IV (3) or had progressive stage II disease (1). Three pts were treated in cohort 1; 2 pts completed 6 cycles, but 1 pt was removed from study after cycle 3 due to prolonged cytopenias. Six pts were treated in cohort 2. Two pts developed dose-limiting toxicity; 1 pt developed grade 3 confusion and grade 3 generalized seizures during cycle 2, and 1 pt developed nausea and diarrhea, which resulted in grade 3 acute renal failure. Infectious toxicity was limited to 1 pt who was hospitalized for 48 hrs with a grade 3 upper respiratory infection and febrile neutropenia. Three pts in cohort 2 were removed from study for prolonged cytopenias after 3, 3 and 4 cycles; only 1 pt in cohort 2 completed 6 cycles. Two of the 6 pts in cohort 2 did not receive flavopiridol after cycles 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Response was graded by NCI 96 criteria (CLL) or IWG criteria (MCL/FL). Overall response rate (ORR) was 100%; 7 pts (78%) achieved CR, and 2 pts achieved PR (22%). Two pts relapsed after 7 and 8 months; 7 pts remain in remission a median of 9 (range,7–12) months after therapy. Of note, all 4 MCL/FL pts remain in CR. An ongoing expansion of 12 pts at the cohort 1 dose level is being conducted, to better define toxicity and efficacy; 6 pts have been enrolled to date. In conclusion, flavopiridol, fludarabine and rituximab exhibited significant clinical activity in a small group of pts, with a 78% CR rate. This combination warrants further study, particularly with consideration to an altered flavopiridol schedule using our highly active 30-minute bolus followed by 4-hour infusion regimen.

Flavopiridol, Fludarabine and Rituximab Is a Highly Active Regimen in Indolent B-Cell Lymphoproliferative Disorders Including Mantle Cell Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 944-944 ◽  
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Mollie E. Moran ◽  
Maureen M. Buckner ◽  
Roshini Shank ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Stage Iii ◽  
Clinical Activity ◽  
Mantle Cell ◽  
Grade 3

Abstract The cyclin-dependent kinase inhibitor flavopiridol was inactive when given by 24–72-hr infusion, but 1-hr IV bolus dosing demonstrated clinical activity in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Flavopiridol induces apoptosis independent of p53 and may be able to eliminate tumor cells resistant to fludarabine and rituximab. We performed a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with MCL, CLL and indolent B-cell non-Hodgkin’s lymphoma (NHL). Pts had ANC ≥ 1500, hemoglobin ≥ 9.0, platelets ≥ 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. The planned dose escalation of flavopiridol was 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1), day 1–2 (cohort 2), or day 1–3 (cohort 3) of each cycle. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was prohibited. Twenty-one pts were enrolled and are evaluable for toxicity and response. Median age was 62 years (range, 43–81), and 10 pts were male. Pts had the following diagnoses: CLL (8), MCL (5), follicular lymphoma (FL; 4), small lymphocytic lymphoma (SLL; 3), and lymphoplasmacytic lymphoma (1). Nine pts had received 1-2 prior therapies; 12 pts were previously untreated. CLL pts were Rai stage III/IV (5) or required treatment for Rai stage I/II disease (3) by NCI 96 criteria. NHL pts were stage III/IV (10) or had progressive stage II disease (3). Three pts were treated in cohort 1, and dose limiting toxicity (DLT) was not observed. Six pts were treated in cohort 2. Two pts developed DLT; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Three pts in cohort 2 did not receive flavopiridol after cycles 2, 2 and 3, due to life threatening tumor lysis in our single agent flavopiridol study. Twelve additional pts were enrolled at the cohort 1 dose level, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 9 of 21 pts completed all 6 planned cycles. Therapy was stopped early due to cytopenias (7), infection (2), DLT (2) or progressive disease (1). One patient who received only 2 cycles of FFR due to cytopenias subsequently received 4 cycles of fludarabine and rituximab from his local oncologist. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 90%; 15 pts achieved CR (71%), and 4 pts achieved PR (19%). Six pts relapsed a median of 7.5 months (range 4–18) after completing therapy; 13 pts remain in remission a median of 11 months (range 4–23) after completing therapy. Of note, all 9 MCL/FL pts responded (8 CR, 1 PR), and 8 pts remain in remission a median of 15 months (6–23) after finishing therapy. In conclusion, FFR exhibited significant clinical activity in a small group of pts, but cytopenias limited the administration of therapy. We are currently studying a modified FFR regimen administering a more active flavopiridol schedule (30-min IV bolus followed by 4-hr IV infusion) and allowing the use of prophylactic filgrastim, prior to phase II clinical study.

Flavopiridol, Fludarabine and Rituximab (FFR): An Active Regimen in Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1571-1571 ◽  
Author(s):  
Thomas S. Lin ◽  
Beth Fischer ◽  
Kristie A. Blum ◽  
Pierluigi Porcu ◽  
Eric H. Kraut ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Response Rate ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Mantle Cell ◽  
Grade 3

Abstract Background: The cyclin-dependent kinase inhibitor flavopiridol (alvocidib) induces p53-independent apoptosis and may be able to eliminate tumor cells resistant to fludarabine and rituximab. Study Design and Treatment: We report final results of a phase I dose escalation study of flavopiridol in combination with fludarabine and rituximab (FFR) in patients (pts) with mantle cell lymphoma (MCL), indolent B-cell non-Hodgkin’s lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL). Pts had ANC 3 1500, hemoglobin 3 9.0, platelets 3 100,000, adequate organ function, and ECOG performance status 0–2, and provided informed consent. Pts received fludarabine 25 mg/m2 IV on day 1–5 and rituximab 375 mg/m2 on day 1 every 28 days for up to 6 cycles. Flavopiridol was administered 50 mg/m2 by 1-hr IV bolus on day 1 (cohort 1, n=15) or day 1 and 2 (cohort 2, n=6) of each cycle. Based on promising results with a novel single agent dosing schedule in CLL, the study was amended to give flavopiridol by 30-min IV bolus followed by 4-hr IV infusion at a dose of 20 mg/m2 + 20 mg/m2 (cohort 3, n=3) or 30 mg/m2 + 30 mg/m2 (cohort 4, n=14) beginning with cycle 2. Pts were placed on prophylactic Bactrim and Valtrex. Growth factor support was allowed in cohorts 3 and 4. Results: Thirty-eight pts were enrolled. Median age was 62 years (range, 38–81), and 22 pts were male (58%). Pts had CLL (11), MCL (10), follicular (FL, 9), small lymphocytic (3), marginal zone (4) or lymphoplasmacytic lymphoma (1). Sixteen pts had received 1 or 2 prior therapies; 22 pts were previously untreated. Two of 6 pts in cohort 2 developed dose limiting toxicity; 1 pt developed grade 3 confusion and grade 3 seizures, and 1 pt developed nausea and diarrhea resulting in grade 3 acute renal failure. Fifteen pts were enrolled in cohort 1 and 14 pts were enrolled in cohort 4, to better define toxicity and efficacy. Pts received a median of 4 cycles (range 1–6), and 16 of 38 pts completed all 6 planned cycles. Cytopenias (10), fatigue (3), fever (2) and progression (2) were the most common reasons for early discontinuation of therapy. Response was graded by NCI 96 criteria (CLL) or IWG criteria (NHL). Overall response rate (ORR) was 82% (CR 50%, CRu 5%, PR 26%). Median progression-free survival (PFS) of responders was 25.5 months. ORR (82% vs. 81%), CR (50% vs. 50%) and median PFS (25.7 vs. 25.1 months) were similar for previously untreated and relapsed pts. Thirteen pts remain in remission with a median PFS of 33.5 months (range, 17.5–59.5), and 3 other pts died of unrelated causes. Eight of 10 MCL pts (median age 68, range 62–81) responded (7 CR, 1 PR). Two responders with blastoid variant MCL relapsed within 1 year, but median PFS of the other 6 responding MCL pts was 33.5 months. All 9 FL pts responded (5 CR, 2 CRu, 2 PR) with a median PFS of 25.1 months (range, 4.0–46.3). Conclusions: FFR exhibited significant clinical activity in indolent B-NHL, MCL and CLL. FFR was effective in both relapsed and previously untreated pts and showed promising clinical activity in older MCL pts. Changing from 1-hr IV bolus dosing to 30- min IV bolus followed by 4-hr IV infusion did not improve the response rate, suggesting that 1-hr IV bolus dosing may be effective when flavopiridol is given as part of combination chemotherapy. This regimen warrants further study.

CD5+ B-cell lymphoproliferative disorders: Beyond chronic lymphocytic leukemia and mantle cell lymphoma

2010 ◽  
Vol 34 (9) ◽  
pp. 1235-1238 ◽  
Author(s):  
Dragan Jevremovic ◽  
Roxana S. Dronca ◽  
William G. Morice ◽  
Ellen D. McPhail ◽  
Paul J. Kurtin ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
Lymphocytic Leukemia ◽  
Mantle Cell

A Phase I/II Study of Vorinostat (SAHA), Cladribine (2-CdA), and Rituximab Shows Significant Activity in Previously Untreated Mantle Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 441-441 ◽  
Author(s):  
Stephen Spurgeon ◽  
Andy I Chen ◽  
Craig Okada ◽  
Samir Parekh ◽  
Violetta V. Leshchenko ◽  
...  
Keyword(s):  
Cell Death ◽  
Phase I ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Dna Hypomethylation ◽  
Tumor Cell Death ◽  
B Cell Malignancies ◽  
Mantle Cell ◽  
Correlative Studies

Abstract Abstract 441 Background: Despite significant progress in the treatment of mantle cell lymphoma (MCL), relapse remains the norm and additional therapies are needed especially for patients who are not candidates for aggressive treatment approaches. Increasingly, it has become evident that epigenetic modifications, including DNA hypomethylation and histone deacetylase inhibition, are critical to the pathogenesis and treatment of hematologic malignancies; important to cancer biology; and may be essential to the development of treatment resistance in B-cell malignancies. Further development and understanding of new and effective treatment regimens that target the epigenome are needed. 2-CdA has activity in a variety of B and T cell malignancies. In addition to its cytotoxic effects, our preliminary work shows that 2-CdA has hypomethylating properties in lymphoid malignancies. When primary MCL and CLL cells -before and 96 hours after cladribine treatment-were analyzed by HELP (HpaII tiny fragment Enrichment by Ligation mediated PCR), an array based genome-wide methylation assay, 2-CdA affected DNA hypomethylation. One of the genes hypomethylated was identified as DUSP2, a dual specificity phosphatase gene that is a p53 target gene. DUSP2 dephosphorylates phosphoserine/threonine and phosphotyrosine residues, negatively regulating mitogen-activated protein (MAP) kinases ERK1 and ERK2, which are associated with cellular proliferation and differentiation in B-NHL. Vorinostat (SAHA) is a histone deacetylase inhibitor (HDACi), which has shown modest single agent activity in lymphoma and is FDA approved for use in cutaneous T cell lymphoma (CTCL). MCL cell lines treated with cladribine activated DUSP2 mRNA and when treated with the HDAC inhibitor SAHA synergistically increased transcription of DUSP mRNA. Furthermore, MCL treated with cladribine in vitro showed inhibition of global histone methylation. Our hypothesis is that cladribine and vorinostat synergistically activate silenced genes such as but not limited to DUSP 1 and 2 that are important for tumor cell death. The mechanism of rapid tumor cell death is under investigation, and does not appear to involve the classical apoptosis pathway. Given the need for novel therapies and the potential synergy seen with 2-CdA and SAHA, we initiated a Phase I/II trial combining SAHA, 2-CdA, and rituximab (SCR) for the treatment of B-cell non-Hodgkin's Lymphoma (NHL). The Phase I portion has been completed while Phase II is actively enrolling patients including those with newly diagnosed MCL. Methods: Phase I enrolled 10 patients with relapsed/refractory NHL. The MTD of vorinostat for the Phase I was 400 mg (D 1–14) combined with 2-CdA 5mg/m2 IV (D 1–5), and R 375 mg/m2 IV (weekly × 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Phase II eligibility includes relapsed NHL as well as previously untreated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Primary outcome is response rate (ORR). Scientific correlatives include analysis of CD20 expression, histone acetylation, gene microarray and HELP methylation analysis, ERK phosphorylation, and Q-PCR of potential target genes. Results: 52 patients (Phase I/II) have been enrolled and 45 patients have been treated. The ORR in evaluable relapsed patients (3 DLBCL, 10 MCL, 1 FL, 1 MZL, 7 CLL) is 32% (7/22). Among these relapsed patients, complete remissions (CR) have been observed in MCL as well as follicular and marginal zone lymphomas. Of the 20 previously untreated MCL patients, 19 have completed ≥ 2 cycles and are evaluable for response. ORR is 100% (19/19) with 79% (15/19) CR. Toxicities by CTCAE 3.0 criteria have primarily included reversible myelosuppression, fatigue, dehydration, 1 gr. 4 thrombo-embolic event (probably related), and 1 grade 5 pulmonary hemorrhage in a patient with relapsed pulmonary lymphoma. One previously untreated mantle cell lymphoma patient has ongoing Gr. 3 thrombocytopenia six weeks after completing therapy. Preliminary analysis of ongoing correlative studies is available in 1 MCL patient and shows DUSP2 upregulation. Conclusions: The SCR regimen shows activity across a number of B-cell malignancies and shows particular therapeutic promise in patients with previously untreated mantle cell lymphoma. Correlative studies are ongoing and will be presented. Future studies should continue to explore this regimen in previously untreated mantle cell lymphoma. Disclosures: Off Label Use: vorinostat (SAHA) is not FDA approved for the treatment of B cell lymphomas. Okada:Merck: Speakers Bureau. Epner:Merck: Speakers Bureau.

T3 : A Multicenter Phase IB Dose Escalation Study to Evaluate the Safety, Feasibility and Efficacy of the Temsirolimus (Torisel™)-CHOP-Rituximab (T-R-CHOP), Temsirolimus (Torisel™)-FC-Rituximab (T-R-FC) and Temsirolimus (Torisel™)- DHA-Rituximab (T-R-DHA) for the Treatment of Patients with Relapsed/Refractory Mantle Cell Lymphoma (MCL), a Lysa Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4426-4426
Author(s):  
Steven Le Gouill ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
Remy Gressin ◽  
Thierry Lamy ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Chemotherapy Regimen ◽  
Cell Lymphoma ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Multicenter Phase ◽  
Mantle Cell ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract The T3 trial is a multicenter Phase IB dose escalation study that evaluates the safety, feasibility and efficacy of three Temsirolimus-based chemotherapy regimens: Temsirolimus(Torisel™)-CHOP-Rituximab (T-R-CHOP), Temsirolimus(Torisel™)-FC-Rituximab (T-R-FC) and Temsirolimus(Torisel™)-Dexamethasone-aracytine-Rituximab (T-R-DHA) for the treatment of patients with relapsed/refractory Mantle Cell Lymphoma (MCL). The choice of the chemotherapy regimen was left to the decision of local investigator. The primary objective of the T3 was to assess the feasibility and incidence of dose limiting toxicities (DLT) during the two first cycles for each chemotherapy regimen in order to determine the maximal tolerate dose (MTD) in a 3+3 dose escalating design. Dose levels of Temsirolimus (administrated at D2, 8 and 15) were as followed: 25mg level 1; 50mg level 2 and 75mg level 3 and 15 mg in level -1. Patients were planned to receive at least 4 cycles. After 4 cycles, response was evaluated and then patients could continue treatment for 2 additional cycles or receive another treatment according to investigator’s decision. The T3 trial started in November 2011 and so far 38 patients have been enrolled (32 patients are evaluable to date; median age of 69y; range 56 -79). Before inclusion into the T3 trial, patients had received a median of 1 (range 1-3) line of treatment including autologous stem cell transplantation in 15 cases. Nine patients were included in the R-CHOP group (ORR after 4 cycles was 55,6%). In level 1, two patients out of 3 experimented DLT (grade 3: lymphopenia and GI hemorrhage). In level -1 (n=6), one DLT has been reported (grade 3 thrombocytopenia). In the T-R-FC group (n=12; ORR after 4 cycles was 41,7%), 6 patients were included in level 1 and 3 experimented DLT (grade 3: thrombocytopenia and leukopenia). In cohort -1 (n=6), 4 DLTs were reported. Eleven patients were included in the T-R-DHA group (ORR after 4 cycles was 80%). One DLT was suspected during toxicity review in level 1 (n=3) and was not confirmed as a DLT by the Safety Committee, hence the decision to pass to superior dose level. Then 6 patients (3+3) were included in level 2 (50mg) where 1 DLT was reported. However, only one patient received complete schema of temsirolimus with 3 injections because of hematology toxicity. Thus, it has been decided to add 3 additional patients at level 1 (25mg). These patients are currently under treatment. In conclusion, hematological toxicity grade 3 was the major concern of the three temsirolimus-based chemotheprapy regimen. Administration of Temsirolimus at D15 was frequently skipped. However, 51,6% of patients reached at least a PR after 4 cycles and the T-R-DHA group was the safest, in which, 50% of patients reached CR after 4 cycles. Thus, Temsirolimus plus high dose aracytine based-chemotherapy regimens provides good disease control with an acceptable tolerability profile for patients with relapsed MCL. Disclosures Le Gouill: pfizer: Honoraria; mundipharma: Honoraria; roche: Honoraria; celgene: Consultancy, Honoraria; janssen-cilag: Honoraria. Coiffier:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Phase I and pharmacokinetic study of bendamustine hydrochloride in relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma

2010 ◽  
Vol 101 (9) ◽  
pp. 2054-2058 ◽  
Author(s):  
Michinori Ogura ◽  
Toshiki Uchida ◽  
Masafumi Taniwaki ◽  
Kiyoshi Ando ◽  
Takashi Watanabe ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Hodgkin Lymphoma ◽  
Pharmacokinetic Study ◽  
Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Mantle Cell

scholarly journals A Phase I Trial of Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 150-150 ◽  
Author(s):  
Peter Martin ◽  
Kristie Blum ◽  
Nancy L. Bartlett ◽  
Steven I. Park ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hematological Toxicity ◽  
Mantle Cell ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Levels

Abstract Background Single-agent ibrutinib confers a response rate of 77%, including a complete response (CR) rate of 19% in patients with previously treated mantle cell lymphoma (MCL); however, with a median progression-free survival (PFS) of 14.6 months and 1-year response duration (RD) rate of 69%, nearly half of all patients experience treatment failure during the first year. We previously demonstrated that prolonged early G1 cell cycle arrest induced by the oral, specific CDK4/6 inhibitor palbociclib can overcome ibrutinib resistance in primary human samples and MCL cell lines with wild-type BTK (Chiron et al. Cancer Discovery 2014). We conducted a phase I trial to evaluate the safety and preliminary activity of palbociclib plus ibrutinib in patients with previously treated mantle cell lymphoma. Methods Adult patients who were ibrutinib and CDK4/6 inhibitor-naïve who had previously treated MCL were eligible to participate. The primary objective was to estimate the maximum tolerated dose of the combination. Consenting patients were enrolled to one of five dose levels, shown in Table 1. Patients were treated in 28 day cycles, with ibrutinib administered daily and palbociclib administered on days 1-21. (Table 1). Patients could continue to receive study treatment until progression, unacceptable toxicity, or withdrawal of consent. Doses were escalated according to a standard phase I 3+3 design. Patients were evaluated for efficacy at the end of cycles 3 and 6, and every 6 cycles thereafter. All CRs, as documented by CT, required confirmation by PET/CT; bone marrow biopsy and endoscopy were also required in patients with known marrow or GI tract involvement, respectively. Additional objectives included pharmacokinetics and evaluation of pretreatment samples for biomarkers of response or resistance. Results From August 2014 to June 2016 a total of 20 patients (15 males, 5 females) were enrolled (DL1 n=3, DL2 n=3, DL3 n=6, DL4 n=3, DL5 n=5). The patients' MIPI risk distribution were 7 low, 7 intermediate, and 6 high. The median number of prior therapies was 1 (range 1-5). Six patients were refractory to their last prior therapy. Three patients experienced dose limiting toxicity: One patient treated at DL3 experienced grade 4 thrombocytopenia lasting more than 7 days, and grade 3 rash was seen in two patients at DL5. Grade 3-4 hematological toxicity included thrombocytopenia (28%), neutropenia (22%), and lymphopenia (17%). Grade 3-4 non-hematological toxicity regardless of attribution included one patient with each of the following: lung infection, ALT/AST increase, encephalitis, hyponatremia, sinus tachycardia, pneumonitis. Grade 1-2 adverse events related to treatment and occurring in at least 2 patients included the following: diarrhea (50%), fatigue (44%), rash (39%), bruising (17%), nausea (17%), fever (11%), dyspepsia (11%), and myalgia (11%). Other than the two patients that experienced grade 3 rash at DL5, no patients have required dose reductions; 6 patients required dose interruptions. Thirteen subjects continue on study therapy. The reasons for stopping treatment were disease progression (n=4), adverse event (elevated liver enzymes, n=1; and prolonged cytopenias, n=1), and allogeneic stem cell transplantation (n=1). Of the 18 patients that have had at least one response evaluation to date, 12 (67%) patients responded to treatment and 8 (44%) achieved a CR. The median time to CR was 3 cycles and no responding patients have progressed on study. With a median follow up of 11 months, the estimated 1-year PFS and RD are 68% and 100%, respectively (Figure 1). Conclusions The mechanism-based combination of ibrutinib plus palbociclib is well tolerated and active. Toxicity is primarily related to myelosuppression of grade 1-2 severity, although grade 3 rash was observed at the highest doses evaluated. In this small group of patients, the combination produced responses at all dose levels, with a CR rate of 44% and a median time to CR of 3 months. No responding patients have progressed to date. These preliminary CR, PFS, and RD rates appear better than those reported in other studies of single-agent ibrutinib although the numbers of patients was very small. A phase II multi-center clinical trial to evaluate time to progression is planned. Biomarker studies to evaluate mechanisms of primary resistance are ongoing. Disclosures Martin: Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy; Acerta: Consultancy; Teva: Research Funding. Ruan:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics, LLC, an AbbVie Company: Research Funding, Speakers Bureau; Janssen: Research Funding.

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