ALRN-6924 and Palbociclibin Patients with MDM2 Amplified or...
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ALRN-6924 and Palbociclib in Patients with MDM2 Amplified or MDM2/CDK4 Co-amplified Tumors: Interim Analysis Funda Meric-Bernstam 1 , Neeta Somiah 2 , Steven G. DuBois 3,4 , Ecaterina Ileana Dumbrava 1 , Geoffrey Shapiro 3 , Manish R. Patel 5 , Sanjay Goel 6 , Todd Bauer 7 , Dawn Pinchasik 8 , Allen Annis 8 , Manuel Aivado 8 , Vojislav Vukovic 8 , Mansoor Saleh 9 1 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Boston Children’s Hospital, Boston, MA; 5 Florida Cancer Specialists and Research Institute, Sarasota, FL; 6 Montefiore Einstein Cancer Center, Bronx, NY; 7 Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; 8 Aileron Therapeutics Inc., Watertown, MA; 9 University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL ALRN-6924 is a stabilized, cell-permeating alpha-helical peptide that mimics the p53 tumor suppressor protein to disrupt p53’s interactions with its endogenous inhibitors, MDM2 and MDMX (Figure 1A). ALRN-6924 has been evaluated in >175 cancer patients and demonstrated single-agent activity and a well-tolerated single-agent safety profile. 1-3 MDM2 amplification is an oncogenic event found in up to 4% of all cancers. Co-amplification of MDM2 and cyclin- dependent kinase 4 (CDK4), which are co-located on chromosome 12q13 (Figure 1B), provides the rationale for combined use of the MDM2-inhibitor ALRN-6924 and the CDK4/6 inhibitor palbociclib in this population, and is further supported by enhanced combination activity in preclinical models (Figure 1C). Background Table 1: Demographic and Clinical Characteristics Conclusions • This interim analysis shows the combination of ALRN-6924 and palbociclib is very well tolerated and has a good safety profile in patients with MDM2 amplified or MDM2/CDK4 co-amplified tumors • Preliminary efficacy was observed in patients with locally advanced or metastatic liposarcomas, supporting the hypothesis that dual-targeting MDM2/CDK4 co-amplified patients with ALRN-6924 + palbociclib may result in clinical activity • Further development of this combination in liposarcoma patients is warranted ESMO Congress 2019: September 27 – October 1, 2019, Barcelona, Spain 490 Arsenal Way - Watertown, MA 02472, USA | Phone: 617-995-0900 | Fax: 617-995-2410 | [email protected] Results This is a multicenter, open-label, Phase 2a expansion cohort of an ongoing Phase 1 clinical trial that is enrolling MDM2 amplified or MDM2/CDK4 co-amplified cancer patients (ClinicalTrials.gov NCT02264613). This Phase 2a trial is designed to enroll 25 patients with solid tumors harboring wild-type p53 and MDM2 amplification or MDM2/CDK4 co-amplifications. Patients have exhausted or are not eligible for other treatment options. ALRN-6924 is given at a dose of 3.1 mg/kg as IV infusion on Days 1, 8 and 15, and palbociclib is given as an oral dose of 100 mg/day on Days 1-21 of every 28-day treatment cycle. The first nine patients enrolled were evaluated for safety and tolerability after completion of one treatment cycle (safety lead-in). Anti-tumor activity is evaluated with imaging every 8 weeks. Treatment Schedule D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 D17 D18 D19 D20 D21 D22 D23 D24 D25 D26 D27 D28 Table 2: Adverse Events and Serious Adverse Events Palbociclib 100mg daily ALRN-6924 3.1 mg/kg Treatment free Figure 2: Duration of Exposure for All Enrolled Patients (N=26) Figure 3: Activity in Liposarcoma Patients (N=17)† Figure 4: Liposarcoma Patients PFS p53 ALRN-6924 (low dose) p53 ALRN-6924 (high dose) Cell Cycle Arrest Cell Death Low Levels High levels Cell Cycle Arrest High Levels Cell Death Figure 1: The Dual MDM2/MDMX Inhibitor ALRN-6924 Activates p53 to Induce Cell Cycle Arrest and Apoptosis, and Synergizes with the CDK4/6 Inhibitor Palbociclib Methods Primary Objectives • Evaluation of safety and tolerability of the ALRN-6924 and palbociclib combination • Assessment of objective tumor response rate Secondary Objectives • Evaluation of PK for ALRN-6924 and its metabolites, and palbociclib • Evaluation of additional measures of efficacy, including DOR, PFS and OS 1. Meric-Bernstam F. et al., Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas, J. Clin. Oncol. 35 (15):2505-2505 (2017). 2. Meric-Bernstam F. et al., ASCO 2017 presentation: http ://share.aileronrx.com/presentations/ALRN-6924_Final_Slides_ASCO_02Jun2017.pdf. 3. Shustov, A. R., et al. Preliminary results of the stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, in two phase IIa dose expansion cohorts in relapsed/refractory TP53 wild-type peripheral T-cell lymphoma. Blood 132(Suppl 1),1623 (2018). 4. B.A. Van Tine, "Multiple Molecular Subtypes of Sarcoma Allow for Orphan Drug Development," The Journal of Targeted Therapies in Cancer 2016. 5. Annis et al, “The Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, and the CDK4/6 Inhibitors Palbociclib, Ribociclib, or Abemaciclib Synergistically Enhance Each Other’s in vitro and in vivo Anticancer Activity,” San Antonio Breast Cancer Symposium 2018. References A) ALRN-6924 can induce two distinct p53-effects: cell-cycle arrest or cell death. B) Co-amplification of MDM2 and cyclin-dependent kinase 4 (CDK4) occurs frequently; both events have oncogenic potential. 4 C) Combination of the MDM2-inhibitor ALRN-6924 and the CDK4/6 inhibitor palbociclib has synergistic activity in preclinical cancer models. 5 A B C Characteristic All patients N=26 (100%) Liposarcoma patients N=17 (100%) † Gender Male 16 (62) 10 (59) Female 10 (39) 7 (41) Age Median (range) 59 (27,79) 58 (41, 75) ECOG PS at Study Entry 0 5 (19) 4 (24) 1 21 (81) 13 (76) Predominant Histology WDLPS - 5 (29) DDLPS - 8 (47) WDLPS+DDLPS - 3 (18) Unknown - 1 (6) Metastatic Disease Yes 16 (94) No 1 (6) Number of Prior Systemic Therapy Regimens 1 8 (31) 8 (47) ≥2 17 (65) 8 (47) none 1 (4) 1 (6) MDM2/CDK4 Amplification MDM2 amplified 4 (15) 2 (12) MDM2/CDK4 co-amplified 17 (65) 15 (88) Missing 5 (19) - Related AE All Grades N=26 (100%) Grade 3-4 N=26 (100%) Neutropenia 13 ( 50) 7 (27) Nausea 12 ( 46) 0 Thrombocytopenia 7 ( 27) 1 (4) Fatigue 6 ( 23) 0 Leukopenia 5 ( 19) 1 (4) Vomiting 5 ( 19) 0 Anemia 3 ( 12) 0 Decreased appetite 3 ( 12) 0 Dysgeusia 3 ( 12) 0 Related SAE Grade N=26 (100%) Neutropenia 4 1 (4) Thrombocytopenia 4 1 (4) Pulmonary embolism 4 1 (4) †Efficacy-evaluable population includes 17 liposarcoma patients having ≥1 post-baseline radiological assessment, MDM2 amplification, and TP53-WT. Excludes patients pending 1 st post-baseline radiological assessment (n=4), mutant TP53 (n=2), glioblastoma (n=2, discontinued for adverse event; clinical disease progression), and osteosarcoma (n=1, objective disease progression, received new therapy before CT scan). PFS N=17 (%) PFS events, N (%) PD 8 (47) Death 0 Censored 9 (53) PFS rate at 3 months, % (95% CI) 73 (42, 89) Median PFS, months (95% CI) 4.4 (2.0, NE) Figure 5: All Patients PFS On treatment Off treatment †Efficacy-evaluable liposarcoma patients having ≥1 post-baseline radiological assessment, MDM2 amplification, and TP53-WT as of 02-Sep-2019 data cutoff. Best Percentage Change in Sum of Diameters From Baseline 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 PFS N=26 (%) PFS events, N (%) PD 8 (31) Death 0 Censored 18 (69) PFS rate at 3 months, % (95% CI) 74 (43, 89) Median PFS, months (95% CI) 4.4 (2.7, NE) Days 0 20 40 60 80 100 120 140 160 180 200 220 240 Gallbladder Adenocarcinoma Glioblastoma Liposarcoma Liposarcoma Glioblastoma Liposarcoma Gastric Adenocarcinoma Liposarcoma Liposarcoma Osteosarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Pleiomorphic Sarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma Liposarcoma 0 3 6 9 0 0.5 1.0 Months Progression-Free Probability 0 3 6 9 0 0.5 1.0 Months Progression-Free Probability 0 200 400 600 800 1000 1200 0 10 20 30 40 50 60 Median MCF-7 Tumor Volume (mm 3 ) Day Vehicle ALRN-6924 10mg/kg Palbociclib 75mg/kg ALRN-6924 10mg/kg + Palbociclib 75mg/kg Dosing period ALRN-6924 20mg/kg + Palbociclib 75mg/kg Best Overall Response per Investigator Assessment Progressive Disease Stable Disease
Transcript of ALRN-6924 and Palbociclibin Patients with MDM2 Amplified or...
ALRN-6924 and Palbociclib in Patients with MDM2 Amplified or MDM2/CDK4 Co-amplified Tumors: Interim AnalysisFunda Meric-Bernstam1, Neeta Somiah2, Steven G. DuBois3,4, Ecaterina Ileana Dumbrava1, Geoffrey Shapiro3, Manish R. Patel5, Sanjay Goel6, Todd Bauer7, Dawn Pinchasik8, Allen Annis8, Manuel Aivado8, Vojislav Vukovic8, Mansoor Saleh9
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; 3Dana-Farber Cancer Institute, Boston, MA; 4Boston Children’s Hospital, Boston, MA; 5Florida Cancer Specialists and Research Institute, Sarasota, FL; 6Montefiore Einstein Cancer Center, Bronx, NY; 7Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; 8Aileron Therapeutics Inc., Watertown, MA; 9University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL
ALRN-6924 is a stabilized, cell-permeating alpha-helical peptide that mimics the p53 tumor suppressor protein to disruptp53’s interactions with its endogenous inhibitors, MDM2 and MDMX (Figure 1A). ALRN-6924 has been evaluated in >175cancer patients and demonstrated single-agent activity and a well-tolerated single-agent safety profile.1-3
MDM2 amplification is an oncogenic event found in up to 4% of all cancers. Co-amplification of MDM2 and cyclin-dependent kinase 4 (CDK4), which are co-located on chromosome 12q13 (Figure 1B), provides the rationale for combineduse of the MDM2-inhibitor ALRN-6924 and the CDK4/6 inhibitor palbociclib in this population, and is further supported byenhanced combination activity in preclinical models (Figure 1C).
BackgroundTable 1: Demographic and Clinical Characteristics
Conclusions• This interim analysis shows the combination of ALRN-6924 and palbociclib is very well tolerated and has a good safety
profile in patients with MDM2 amplified or MDM2/CDK4 co-amplified tumors
• Preliminary efficacy was observed in patients with locally advanced or metastatic liposarcomas, supporting the hypothesis that dual-targeting MDM2/CDK4 co-amplified patients with ALRN-6924 + palbociclib may result in clinical activity
• Further development of this combination in liposarcoma patients is warranted
ESMO Congress 2019: September 27 – October 1, 2019, Barcelona, Spain490 Arsenal Way - Watertown, MA 02472, USA | Phone: 617-995-0900 | Fax: 617-995-2410 | [email protected]
Results
This is a multicenter, open-label, Phase 2a expansion cohort of an ongoing Phase 1 clinical trial that is enrolling MDM2amplified or MDM2/CDK4 co-amplified cancer patients (ClinicalTrials.gov NCT02264613).
This Phase 2a trial is designed to enroll 25 patients with solid tumors harboring wild-type p53 and MDM2 amplification orMDM2/CDK4 co-amplifications. Patients have exhausted or are not eligible for other treatment options. ALRN-6924 isgiven at a dose of 3.1 mg/kg as IV infusion on Days 1, 8 and 15, and palbociclib is given as an oral dose of 100 mg/day onDays 1-21 of every 28-day treatment cycle. The first nine patients enrolled were evaluated for safety and tolerability aftercompletion of one treatment cycle (safety lead-in). Anti-tumor activity is evaluated with imaging every 8 weeks.
Treatment ScheduleD1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 D17 D18 D19 D20 D21 D22 D23 D24 D25 D26 D27 D28
Table 2: Adverse Events and Serious Adverse Events
Palbociclib 100mg dailyALRN-6924 3.1 mg/kg Treatment free
Figure 2: Duration of Exposure for All Enrolled Patients (N=26)
Figure 3: Activity in Liposarcoma Patients (N=17)†
Figure 4: Liposarcoma Patients PFS
p53
ALRN-6924 (low dose)
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ALRN-6924 (high dose)
Cell CycleArrest
CellDeath
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Highlevels
Cell CycleArrest
HighLevels
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Figure 1: The Dual MDM2/MDMX Inhibitor ALRN-6924 Activates p53 to Induce Cell Cycle Arrest and Apoptosis, and Synergizes with the CDK4/6 Inhibitor Palbociclib
Methods
Primary Objectives• Evaluation of safety and tolerability of the ALRN-6924 and palbociclib combination• Assessment of objective tumor response rate
Secondary Objectives• Evaluation of PK for ALRN-6924 and its metabolites, and palbociclib• Evaluation of additional measures of efficacy, including DOR, PFS and OS
1. Meric-Bernstam F. et al., Phase I trial of a novel stapled peptide ALRN-6924 disrupting MDMX and MDM2-mediated inhibition of WT p53 in patients with solid tumors and lymphomas, J. Clin. Oncol. 35 (15):2505-2505 (2017).2. Meric-Bernstam F. et al., ASCO 2017 presentation: http://share.aileronrx.com/presentations/ALRN-6924_Final_Slides_ASCO_02Jun2017.pdf.3. Shustov, A. R., et al. Preliminary results of the stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, in two phase IIa dose expansion cohorts in relapsed/refractory TP53 wild-type peripheral T-cell lymphoma. Blood132(Suppl 1),1623 (2018).4. B.A. Van Tine, "Multiple Molecular Subtypes of Sarcoma Allow for Orphan Drug Development," The Journal of Targeted Therapies in Cancer 2016.5. Annis et al, “The Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, and the CDK4/6 Inhibitors Palbociclib, Ribociclib, or Abemaciclib Synergistically Enhance Each Other’s in vitro and in vivo Anticancer Activity,” San Antonio Breast Cancer Symposium 2018.
References
A) ALRN-6924 can induce two distinct p53-effects: cell-cycle arrest or cell death. B) Co-amplification of MDM2 and cyclin-dependent kinase 4 (CDK4) occursfrequently; both events have oncogenic potential.4 C) Combination of the MDM2-inhibitor ALRN-6924 and the CDK4/6 inhibitor palbociclib has synergistic activity inpreclinical cancer models.5
A B
C
Characteristic All patients N=26 (100%)
Liposarcoma patients
N=17 (100%) †GenderMale 16 (62) 10 (59)Female 10 (39) 7 (41)AgeMedian (range) 59 (27,79) 58 (41, 75)ECOG PS at Study Entry0 5 (19) 4 (24)1 21 (81) 13 (76)Predominant HistologyWDLPS - 5 (29)DDLPS - 8 (47)WDLPS+DDLPS - 3 (18)Unknown - 1 (6)Metastatic DiseaseYes 16 (94)No 1 (6)Number of Prior Systemic Therapy Regimens1 8 (31) 8 (47)≥2 17 (65) 8 (47)none 1 (4) 1 (6)MDM2/CDK4 AmplificationMDM2 amplified 4 (15) 2 (12)MDM2/CDK4 co-amplified 17 (65) 15 (88)Missing 5 (19) -
Related AE All GradesN=26 (100%)
Grade 3-4 N=26(100%)
Neutropenia 13 ( 50) 7 (27)
Nausea 12 ( 46) 0
Thrombocytopenia 7 ( 27) 1 (4)
Fatigue 6 ( 23) 0
Leukopenia 5 ( 19) 1 (4)
Vomiting 5 ( 19) 0
Anemia 3 ( 12) 0
Decreased appetite 3 ( 12) 0
Dysgeusia 3 ( 12) 0
Related SAE Grade N=26 (100%)
Neutropenia 4 1 (4)
Thrombocytopenia 4 1 (4)
Pulmonary embolism 4 1 (4)
†Efficacy-evaluable population includes 17 liposarcomapatients having ≥1 post-baseline radiological assessment,MDM2 amplification, and TP53-WT. Excludes patientspending 1st post-baseline radiological assessment (n=4),mutant TP53 (n=2), glioblastoma (n=2, discontinued foradverse event; clinical disease progression), andosteosarcoma (n=1, objective disease progression,received new therapy before CT scan).
PFS N=17 (%)PFS events, N (%)
PD 8 (47)Death 0
Censored 9 (53)PFS rate at 3 months, % (95% CI) 73 (42, 89)Median PFS, months (95% CI) 4.4 (2.0, NE)
Figure 5: All Patients PFS
On treatmentOff treatment
†Efficacy-evaluable liposarcoma patients having ≥1 post-baseline radiologicalassessment, MDM2 amplification, and TP53-WT as of 02-Sep-2019 data cutoff.
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Censored 18 (69)PFS rate at 3 months, % (95% CI) 74 (43, 89)Median PFS, months (95% CI) 4.4 (2.7, NE)
Days0 20 40 60 80 100 120 140 160 180 200 220 240
Gallbladder AdenocarcinomaGlioblastomaLiposarcomaLiposarcoma
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Pleiomorphic SarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcomaLiposarcoma
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Best Overall Response per Investigator Assessment
Progressive DiseaseStable Disease
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