Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2581-2581 ◽  
Author(s):  
Rosario García Campelo ◽  
Enriqueta Felip ◽  
Bartomeu Massuti ◽  
Margarita Majem ◽  
Enric Carcereny ◽  
...  
Keyword(s):  
Dose Level ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
Clinical Activity ◽  
Phase Ib ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Egfr Mutant ◽  
Dose Levels ◽  
Egfr Tki

2581 Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3+3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

The combination of EGFR-TKIs and anlotinib as a first-line therapy for EGFR-mutant advanced non-small cell lung cancer: A multicenter, single-arm, phase II clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9030-9030
Author(s):  
Zhiyong He ◽  
Jinghui Lin ◽  
Yueming He ◽  
Jing Zhang ◽  
Dongyong Yang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Advanced Nsclc ◽  
De Novo ◽  
Egfr Mutations ◽  
Treatment Naïve ◽  
Pre Treatment ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tkis

9030 Background: Currently,EGFR-TKIs are widely accepted as the standard treatment for EGFR- mutant advanced non-small-cell lung cancer (NSCLC); however, acquired resistance is inevitable. Combination therapy is considered as a strategy to overcome the resistance to EGFR-TKIs. Anlotinib, a novel multi-targeting, small-molecule TKI, has shown active to suppress tumor angiogenesis and growth. However, there is still a lack of evidence supporting the use of EGFR-TKIs in combination with anlotinib for the treatment of NSCLC until now. A multi-center, single-arm, phase II clinical trial was therefore designed to examine the efficacy and safety of EGFR-TKIs combined with anlotinib for treatment-naïve, advanced NSCLC patients, and unravel the possible mechanisms. Methods: This study was conducted in 14 research centers in Fujian, China. The main eligibility criteria were stage IV or relapsed nonsquamous NSCLC with EGFR mutations (exon 19 deletion,, and L858R), ECOG score 0-2,and age 20 to 75 years and no previous systemic treatment. Patients with asymptomatic brain metastases were admitted.Eligible patients were given gefitinib (250 mg QD) or icotinib (125 mg TID) in combination with anlotinib (10 mg per day, on days 1‒14; 21 days per cycle) until disease progression. The primary endpoint is progression-free survival (PFS) and safety, and the secondary endpoint is overall survival (OS), objective response rate (ORR) and disease control rate (DCR).Peripheral blood was sampled pre-treatment, once every two months during treatment and after disease progression, and T790M mutation was detected in plasma ctDNA using a droplet digital PCR (ddPCR) assay. Results: Of 60 patients enrolled (August 2, 2018 to May 28, 2020). As of February 1, 2021, 37 patients (61.7%) experienced PFS events and 10 (16.7%) died. The ORR was 78.3%, and the DCR was100%.Median PFS was 13.0 months (95%CI,10.7-15.3).The 5 most common treatment-related adverse events included rash (63.3%), fatigue (55.0%), hypertension (48.3%), diarrhea (33.3%) and hand-foot syndrome (30.0%), and grade 3 adverse events included hypertension (5.0%), rash (1.67%), hypertriglyceridemia (1.67%), vomiting (1.67%) and elevated ALT (1.67%); no grade 4 adverse events or drug-related deaths were observed. Peripheral blood samples were collected from 36 patients pre-treatment, and 30.6% were identified with low-frequency de novo T790M mutations, with the mutation-allele frequency (MAF) ranging from 0.01% to 0.28%. Conclusions: The combination of the first-generation EGFR-TKIs and anlotinib shows impressive ORR and DCR, and acceptable toxicity in treatment-naïve advanced NSCLC patients with activating EGFR mutations, and we observed a high proportion of patients harboring de novo EGFR T790M mutations in this study. Clinical trial information: NCT03720873.

CHRYSALIS-2: A phase 1/1b study of lazertinib as monotherapy and in combination with amivantamab in patients with EGFR-mutant NSCLC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9132-TPS9132
Author(s):  
Catherine A. Shu ◽  
Koichi Goto ◽  
Byoung Chul Cho ◽  
Frank Griesinger ◽  
James Chih-Hsin Yang ◽  
...  
Keyword(s):  
Immune Cell ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Egfr Mutations ◽  
Resistance Mutations ◽  
Treatment Naïve ◽  
Phase 1B ◽  
Expansion Cohort ◽  
Egfr Mutant ◽  
Egfr Tki

TPS9132 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have improved clinical outcomes for patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC); however, patients will inevitably progress due to acquired resistance mutations. Lazertinib is a potent, brain-penetrant, 3rd-generation EGFR TKI with efficacy against activating EGFR and resistance T790M mutations. Amivantamab is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating EGFR and MET mutations. Synergistic inhibition of the EGFR by targeting the receptor’s extracellular domain with amivantamab and the kinase domain with lazertinib, may lead to more potent inhibition of the EGFR pathway and potentially delay resistance. In the ongoing CHRYSALIS phase 1 study (NCT02609776), preliminary antitumor activity has been demonstrated with the combination of lazertinib and amivantamab in patients with treatment-naïve and osimertinib-relapsed EGFRm NSCLC (Cho Ann Oncol 2020;31:S813). Methods: CHRYSALIS-2 is an ongoing phase 1/1b open-label study of lazertinib as monotherapy and in combination with amivantamab in patients with advanced EGFRm NSCLC (NCT04077463; https://clinicaltrials.gov/ct2/show/NCT04077463 ). Phase 1 of the study has confirmed the safety and tolerability of lazertinib monotherapy in Japanese patients. The objective of phase 1b is to characterize the preliminary efficacy of lazertinib in combination with amivantamab in subpopulations of patients with EGFRm NSCLC (Phase 1b Expansion Cohorts) at the recommended combination dose of 1050 mg (1400 mg, ≥80 kg) IV amivantamab dosed weekly in cycle 1 (28-day cycle), every other week thereafter, and 240 mg oral lazertinib QD. Global enrollment in Phase 1b Expansion Cohorts is currently ongoing. Expansion Cohort A is enrolling patients who have progressed on 1st or 2nd-line osimertinib followed by platinum chemotherapy; Expansion Cohort B is enrolling patients with EGFR exon 20 insertion (Exon20ins) mutation who have progressed on prior therapy; and Expansion Cohort C is enrolling patients with uncommon non-Exon20ins EGFR mutations (i.e., S768I, L861Q, G719X) who are treatment-naïve or received 1st or 2nd-generation EGFR TKI as last therapy. The primary endpoints of the study are frequency of dose-limiting toxicity for phase 1 and 1b combination cohorts, and overall response rate for phase 1b expansion cohorts. Key secondary endpoints include safety (adverse events), pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, and overall survival. Safety assessments will include monitoring AEs, clinical laboratory tests, ophthalmologic examination, ECG, and ECHO/MUGA. Blood samples will be collected to access PK. Tumor response will be assessed every 6 weeks by the investigator using RECIST, v1.1. Clinical trial information: NCT04077463.

scholarly journals Phase Ib Study of Atezolizumab Plus Interferon-α with or without Bevacizumab in Patients with Metastatic Renal Cell Carcinoma and Other Solid Tumors

2021 ◽  
Vol 28 (6) ◽  
pp. 5466-5479
Author(s):  
Christian U. Blank ◽  
Deborah J. Wong ◽  
Thai H. Ho ◽  
Todd M. Bauer ◽  
Carrie B. Lee ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Solid Tumors ◽  
Renal Cell ◽  
Checkpoint Inhibitor ◽  
Interferon Α ◽  
Clinical Activity ◽  
Phase Ib ◽  
Treatment Naïve ◽  
Previously Treated

This Phase Ib study combined programmed death-ligand 1 inhibitor, atezolizumab, with other immunomodulatory agents in locally advanced and metastatic solid tumors. Arms B-D evaluated atezolizumab plus interferon-α, with/without vascular endothelial growth factor inhibitor, bevacizumab, in renal cell carcinoma (RCC) and other solid tumors. Arm B predominantly recruited patients with previously treated RCC or melanoma to receive atezolizumab plus interferon α-2b. Arm C investigated atezolizumab plus polyethylene glycol (PEG)-interferon α-2a in previously treated RCC. Arm D evaluated atezolizumab plus PEG-interferon α-2a and bevacizumab. Primary objectives were safety and tolerability; secondary objectives included clinical activity. Combination therapy was well tolerated, with safety profiles consistent with known risks of individual agents. The most frequent treatment-related toxicities were fatigue, chills, and pyrexia. The objective response rate (ORR) in arm B was 20.0% overall and 17.8% in patients with previously treated checkpoint inhibitor–naive RCC (n = 45). No responses were reported in arm C. The highest ORR in arm D was 46.7% in patients with treatment-naive RCC (n = 15). Data showed preliminary clinical activity and acceptable tolerability of atezolizumab plus interferon α-2b in patients with previously treated checkpoint inhibitor–naive RCC and of atezolizumab plus PEG-interferon α-2a and bevacizumab in patients with treatment-naive RCC.

Response to EGFR tyrosine kinase inhibitor (TKI) retreatment after a drug-free interval in EGFR-mutant advanced non-small cell lung cancer (NSCLC) with acquired resistance.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7525-7525 ◽  
Author(s):  
Stephanie Heon ◽  
Mizuki Nishino ◽  
Sarah B. Goldberg ◽  
Jennifer Porter ◽  
Lecia V. Sequist ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Single Agent ◽  
Acquired Resistance ◽  
Egfr Mutations ◽  
Free Interval ◽  
Egfr Mutant ◽  
The Impact ◽  
Drug Free ◽  
Egfr Tki

7525 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Anecdotal and retrospective reports suggest that EGFR-TKI resistant cancers can respond again to gefitinib or erlotinib after an interval off the TKI. This retrospective study was undertaken to investigate the impact of EGFR-TKI retreatment after a drug-free interval in EGFR mutant NSCLC with acquired resistance to gefitinib or erlotinib. Methods: Pts with stage IV or relapsed NSCLC with sensitizing EGFR mutations and acquired resistance to EGFR-TKI seen at the DFCI/MGH between 8/00 and 8/11 who were retreated with single agent gefitinib or erlotinib after an EGFR-TKI-free interval were identified from a prospective trial. The objective tumor response (CR, PR, SD, PD) was determined using RECIST 1.1. Results: 19 pts were eligible and had adequate scans for radiographic assessments after the reinstitution of an EGFR-TKI. The response rate and median PFS to the initial course of gefitinib (n=4) or erlotinib (n=15) were 16/19 (84%) and 9.8 months (95% CI, 7.8-11.3) respectively. All pts were retreated with erlotinib after 1 to 4 intervening systemic regimens. The median interval from EGFR-TKI discontinuation to erlotinib retreatment was 11 months (range, 2-46). 4 of the 19 pts (21%) had PD as the best response to erlotinib retreatment, 14 (74%) had SD for at least 1 month, and 1 (5%) had a PR. The median PFS was 4.4 months (95% CI, 3.0-6.7). 3 pts remained on erlotinib without progression for 6 months. 3 pts had their tumors rebiopsied before (n=2) or during (n=1) erlotinib retreatment; 1 of the 3 had EGFR T790M in association with the initial sensitizing EGFR mutation, and another had a secondary PIK3CA mutation. Conclusions: Our findings suggest that erlotinib retreatment is an option for EGFR mutated NSCLC with acquired resistance to EGFR-TKI after a drug-free interval and progression on intervening therapy. Additional advanced NSCLC pts without a documented EGFR mutation who fulfill the clinical definition of acquired resistance are undergoing review to expand our cohort.

Osimertinib (Osi) plus necitumumab (Neci) in EGFR-mutant NSCLC: An ETCTN California cancer consortium phase I study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9057-9057
Author(s):  
Jonathan W. Riess ◽  
Susan G. Groshen ◽  
Karen L. Reckamp ◽  
Heather A. Wakelee ◽  
Geoffrey R. Oxnard ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Sinus Bradycardia ◽  
Clinical Activity ◽  
Recist 1.1 ◽  
Tki Resistance ◽  
Exon 20 ◽  
Egfr Mutant ◽  
Dose Levels ◽  
Egfr Tki ◽  
Clinical Trial Information

9057 Background: Osi (3rd gen EGFR TKI) has robust activity in 1st line EGFR mutant NSCLC and TKI resistant T790Mpos NSCLC but progressive disease (PD) occurs and outcomes with Osi alone are poor in T790Mneg, C797Xpos and EGFR exon 20 insertion (ins20) disease. This study examined the EGFR monoclonal antibody Neci with Osi in select settings of EGFR TKI resistance. Methods: Using a 3+3 design, Neci was examined in advanced EGFR mutant NSCLC at dose levels (DL) of 600 mg (DL1) & 800 mg (DL2) D1, D8 IV q21 days + Osi 80 mg qd. Four expansion cohorts (ExC; 18 each) included: A) T790Mneg PD on 1st/2nd gen TKI as last therapy, B) T790Mneg PD on 3rd gen TKI, C) T790Mpos PD on 3rd gen TKI, D) EGFR ex20ins PD on chemotherapy. Central T790M testing by ddPCR in ExC A-C. Additional studies performed include: NGS panel of > 400 genes, EGFR FISH, plasma for PK and serial EGFR ctDNA by ddPCR as exploratory analyses. Adverse events (AEs) graded (Gr) by CTCAEv5 with ORR and PFS by RECIST 1.1. Results: Dose escalation and ExC B completed accrual. In total 55 pts were evaluable (Table). 1 pt had DLT at DL2, Gr 3 sinus bradycardia. Drug related Gr 3 AEs were seen in 27% (15) of pts, mainly rash (7;13%). ctDNA showed decreased mutant allele frequency with therapy in all pts studied with detected EGFR at baseline, with complete plasma clearance in a pt with detectable C797S. Conclusions: The RP2D (Osi 80 mg qd and Neci 800 mg D1, D8 IV on q21d cycle) is feasible and tolerable. In ExC A,T790Mneg pts with 1st/2nd gen EGFR TKI as last treatment, using curtailed sampling, the pre-specified efficacy signal was reached for Osi + Neci comparing favorably to Osi alone in analogous pts from the AURA trial. Clinical activity was also seen in EGFR-dependent resistance (T790Mpos C797Spos) after PD on 3rd gen TKI and in EGFR ins 20. Clinical trial information: NCT02496663. [Table: see text]

scholarly journals P3.02c-046 Safety, Clinical Activity and Biomarker Results from a Phase Ib Study of Erlotinib plus Atezolizumab in Advanced NSCLC

2017 ◽  
Vol 12 (1) ◽  
pp. S1302-S1303 ◽  
Author(s):  
Charles Rudin ◽  
Andrés Cervantes ◽  
Afshin Dowlati ◽  
Benjamin Besse ◽  
Brigette Ma ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Clinical Activity ◽  
Phase Ib

scholarly journals MA15.02 Long-Term Safety and Clinical Activity Results from a Phase Ib Study of Erlotinib Plus Atezolizumab in Advanced NSCLC

2018 ◽  
Vol 13 (10) ◽  
pp. S407 ◽  
Author(s):  
C. Rudin ◽  
A. Cervantes ◽  
A. Dowlati ◽  
B. Besse ◽  
B. Ma ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Clinical Activity ◽  
Phase Ib

scholarly journals Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Yijia Guo ◽  
Jun Song ◽  
Yanru Wang ◽  
Letian Huang ◽  
Li Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Efficacy ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Gene Alterations

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC

Lung Cancer ◽  
2020 ◽  
Vol 139 ◽  
pp. 133-139 ◽  
Author(s):  
Shuo Yang ◽  
Shiqi Mao ◽  
Xuefei Li ◽  
Chao Zhao ◽  
Qian Liu ◽  
...  
Keyword(s):  
Lower Incidence ◽  
Advanced Nsclc ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Tki Treatment ◽  
Egfr Tki

The Combination Of Palbociclib Plus Bortezomib Is Safe and Active In Patients With Previously Treated Mantle Cell Lymphoma: Final Results Of a Phase I Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4393-4393 ◽  
Author(s):  
Peter Martin ◽  
Maurizio DiLiberto ◽  
Christopher E Mason ◽  
Scott A Ely ◽  
Jia Ruan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dose Level ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
Advisory Committees ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Grade 3 ◽  
Dose Levels

Abstract Introduction Mantle cell lymphoma (MCL) is characterized by cell cycle dysregulation due to cyclin D1 and CDK4 overexpression. Palbociclib (PD 0332991) is an orally bioavailable, specific, reversible inhibitor of CDK4/6 that induces prolonged early G1 arrest (pG1) in MCL cells and durable remissions in patients with MCL. Moreover, we have evidence that palbociclib-induced pG1 sensitizes MCL cells to killing by bortezomib and that sensitization is amplified upon withdrawal of palbociclib, when MCL cells synchronously enter S phase (pG1-S). Targeting CDK4 in combination with bortezomib, therefore, is a rational and novel therapeutic combination. We report the final results of a phase I trial of palbociclib plus bortezomib in patients with previously treated MCL. Methods Adults with previously treated MCL and adequate bone marrow and organ function were received palbociclib orally at doses of 75 mg (dose level 1), 100 mg (dose level 2), or 125 mg (dose levels 3 and 4) for 12 days. Bortezomib was administered by IV or SC injection at 1 mg/m2 (dose levels 1-3) or 1.3 mg/m2 (dose level 4) on days 8, 11, 15, and 18 of each 21-day cycle. Subjects underwent core needle biopsies of tumor tissue pre-treatment, on day 8 (in pG1) and on day 21 (in pG1-S phase) of cycle 1. Subjects were restaged following cycles 2, 5, and 8 and then every 4 cycles. Subjects could remain on the study regimen until progression, unacceptable toxicity, or withdrawal. Dose levels were escalated according to the standard 3+3 schema. Dose limiting toxicity (DLT) was defined as treatment-related grade 3-4 toxicity occurring during cycle 1 or a delay in cycle 2 of > 1 week due to treatment-related grade 4 neutropenia or thrombocytopenia. The primary objective was to estimate the maximum tolerated dose of the combination. Secondary objectives included response rate, duration of response, and evaluation of the pharmacokinetic and pharmacodynamic profiles at multiple time points and across all dose levels. Results Nineteen subjects were enrolled: 6 in dose level 1, 3 in dose level 2, 7 in dose level 3, and 3 in dose level 4. The median age was 64 years (range 42-81). The median number of prior therapies was 3 (range 1-7). The number of subjects with low, intermediate, and high-risk MIPI scores was 6, 11, and 2, respectively. Two subjects experienced DLT: thrombocytopenia (level 1), neutropenia (level 3). Grade 3-4 hematologic toxicity included neutropenia (63%), thrombocytopenia (53%), lymphopenia (32%), and anemia (11%). Treatment-related grade 3-4 non-hematologic toxicity included zoster (1). Grade 1-2 toxicities occurring in >2 pt included: fatigue (47%), pain (42%), bleeding/bruising (37%), increased creatinine (26%), constipation (26%), rash (21%), nausea/vomiting (21%), sensory neuropathy (21%), dyspnea (21%), hypoalbuminemia (16%), cough (16%), edema (16%), infection (16%), increased AST (16%), hypocalcemia (16%), increased alk phos (16%). Reasons for ultimately stopping treatment include: progression (9), toxicity (6), and non-compliance (1). All 3 patients at dose level 4 required dose delays/reductions during cycle 2 due to toxicity. There appeared to be an association with dose of palbociclib and response, with one responder at each of dose levels 1 and 2, and 4 patients remaining free from progression for 1 year at dose level 3, including one complete response. Only one responding patient progressed on therapy. All patients with serial biopsies achieved pG1 on day 8, with reduction in CDK4/CDK6-specific Rb phosphorylation and Ki67 by immunohistochemistry. The primary MCL tumor cells express cell cycle genes scheduled for early G1 such as cyclin D1 and CDK4, but not genes programmed for other phases of the cell cycle such MKi67, E3F3, CDK1, CCNA2, as determined by RNA-seq. Conclusion Daily palbociclib 125 mg for 12 days can be safely combined with bortezomib 1 mg/m2 twice weekly, while higher doses were limited by myelosuppression. The combination induced durable responses in some patients. Palbociclib induced pG1, even at the lowest dose. However, the initial cell cycle control by palbociclib did not predict clinical response. Rather, pG1 appears to induce an imbalance in gene expression that is associated with response to the combination of palbociclib plus bortezomib. Strategies to control the cell cycle and dissect the underpinning mechanisms appear promising in MCL and warrant further evaluation. Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Leonard:Millennium: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document