Abstract
Importance
Over 90% of well-differentiated/de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase 2 study demonstrated that treatment with palbociclib (200mg daily × 14d every 21d) resulted in clinical benefit in WD/DDLS but moderate hematologic toxicity. It is important to understand whether palbociclib at a new dose and schedule, 125mg daily × 21d every 28d, results in clinical benefit and manageable toxicity.
Objective
To determine the progression-free survival (PFS) at 12 weeks of patients with WD/DDLS treated with palbociclib.
Design
Phase 2, non-randomized, open label clinical trial. Patients enrolled from December 2011 to January 2014 and followed to March 2015.
Setting
Memorial Sloan Kettering Cancer Center
Participants
60 patients with advanced WD/DDLS, age ≥ 18 years, and measurable disease by RECIST 1.1 Interventions: Patients received oral palbociclib at 125mg daily for 21 days in 28-day cycles.
Main outcomes and measures
Primary endpoint was PFS. Secondary endpoints included response rate and toxicity.
Results
30 patients were enrolled in the initial cohort and 30 more in an expansion cohort. Median age was 61.5 (range 35–87); 52% were male; median ECOG score was 0 (range 0–1). PFS at 12 weeks was 57.2% (2-sided 95% CI: 42.4% – 68.8%). The median PFS was 17.9 weeks (2-sided 95% CI: 11.9 – 24.0 weeks). There was 1 complete response. Toxicity was primarily hematologic and included neutropenia (grade 3: 33%, grade 4: 3%) but no neutropenic fever.
Conclusions and relevance
In patients with advanced WD/DDLS, treatment with palbociclib was associated with a favorable PFS and occasional tumor response. This dose and schedule appears active and may have less toxicity than 200mg × 14d.
Introduction
Well-differentiated/dedifferentiated liposarcoma (WD/DDLS) is one of the most common types of soft tissue sarcoma.1 Chemotherapy has minimal activity and other than surgery there are limited options for patients with recurrent disease.2 Recent work has identified the oncogene cyclin-dependent kinase 4 (CDK4) as a potential therapeutic target since it is highly amplified in >90% of WD/DDLS3,45,6
Palbociclib is a potent oral inhibitor of CDK4 and CDK6 that prevents downstream phosphorylation of the retinoblastoma (Rb) protein.7,8 Palbociclib inhibits the growth of CDK4-amplified liposarcoma cell lines and xenograft models.9 We previously performed a phase 2 study that demonstrated that treatment with palbociclib (200mg daily × 14 days every 21 days) results in clinical benefit in patients with advanced WD/DDLS but moderate hematologic toxicity.10 30 patients were enrolled and the median PFS was 18 weeks. Aiming to reduce toxicity, we conducted a phase 2 study to assess progression-free survival (PFS) and toxicity with palbociclib at a new dose and schedule, 125mg daily × 21 days every 28 days.
Study Design and Statistical Analysis
This was a non-randomized open-label phase 2 study performed at a single institution. The primary endpoint was progression-free survival (PFS) at 12 weeks. PFS at 12 weeks of > 60% was considered promising and a PFS of < 35% was considered not promising. With a one-stage design, the study would be positive if at least 14 of the first 28 patients were progression-free at 12 weeks, with type I error 0.07 and type II 0.10.11 After the initial cohort completed accrual, the study was extended to include additional patients in an expansion cohort to learn more about the activity of palbociclib in WD/DDLS and to obtain tumor biopsies.
Patients and Methods
Eligible patients were adults with advanced WD/DDLS, ECOG performance status of 0 or 1, and measurable disease by RECIST 1.1.12 In the initial cohort, patients must have received at least one prior systemic treatment; however this was not required in the expansion cohort. In the initial cohort, patients were required to have CDK4 amplification by FISH and RB expression by immunohistochemistry. (The methods and criteria were described previously.10) Since CDK4 amplification is highly prevalent, all of the patients were positive. Thus the requirement for testing was removed for patients in the expansion cohort.
The protocol was approved by the Institutional Review Board of Memorial Sloan Kettering Cancer Center and all patients provided written informed consent.
Treatment
Patients were treated with 125 mg of palbociclib once daily for 21 days, every 28 days. If a cycle had to be delayed by more than 7 days, or grade 4 hematologic toxicity occurred, the dose was reduced to 100 mg, then 75 mg.
Response Assessment
Clinical examinations and laboratory testing were performed at the start of each 28-day cycle for the first 12 cycles, then every other cycle. Tumor response was assessed by a reference radiologist by CT scan every 6 weeks for 36 weeks, then every 12 weeks. Toxicities were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Results
Between December 2011 and April 2013, 30 patients were enrolled in the initial cohort. One patient withdrew consent and is inevaluable for response or PFS. Between April 2013 and January 2014, an additional 30 patients were enrolled in the expansion cohort (See eFigure 1 in the Supplement).
In total 60 patients were treated with palbociclib. All were included in the analysis of safety and adverse events. One patient was inevaluable for response and thus 59 evaluable patients were included in the analysis of response and PFS. The characteristics of all 60 patients enrolled are shown in Table 1. The primary site of disease was the abdomen/retroperitoneum for 97% of patients and 78% had de-differentiated disease. Median age was 61.5 (range 35–87), 52% were male and median ECOG score was 0 (range 0–1). All patients in the initial cohort had received at least one prior systemic treatment, however in the expansion cohort 22 patients (73%) had received no prior systemic treatment. The prior treatments included doxorubicin or liposomal doxorubicin (8), doxorubicin and ifosfamide (6), gemcitabine (5), gemcitabine and docetaxel (13), MDM2 inhibitors (3) and other drugs (11). All of the patients in the initial cohort had CDK4 amplification. In the expansion cohort, 5 patients had CDK4 amplification and the rest were not tested.
Table 1.
Patient Characteristics
| Characteristic | Initial cohort | Expansion cohort | Total |
|---|---|---|---|
| Number | 30 | 30 | 60 |
| Male | 17 (57%) | 14 (47%) | 31 (52%) |
| Female | 13 (43%) | 16 (53%) | 29 (48%) |
| Median Age (Range) | 61.5 (39–86) | 60.5 (35–87) | 61.5 (35–87) |
| ECOG | |||
| 0 | 27 (90%) | 25 (83%) | 52 (87%) |
| 1 | 3 (10%) | 5 (17%) | 8 (13%) |
| Primary site | |||
| Retroperitoneum/abdomen | 29 (97%) | 29 (97%) | 58 (97%) |
| Extremity | 1 (3%) | 1 (3%) | 2 (3%) |
| Histology | |||
| Well-differentiated | 3 (10%) | 10 (33%) | 13 (22%) |
| De-differentiated | 27 (90%) | 20 (67%) | 47 (78%) |
| Prior systemic treatments (#) | |||
| 0 | 0 | 22 (73%) | 22 (37%) |
| 1 | 23 (77%) | 6 (20%) | 29 (48%) |
| ≥2 | 7 (23%) | 2 (7%) | 9 (15%) |
Toxicity
The incidence of Grade 2–4 adverse events possibly, probably, or definitely attributed to palbociclib is shown in eTable 1 (Supplement). The most common toxicities were neutropenia (Grade 3: 33%; Grade 4: 3%), anemia (Grade 3: 22%), and thrombocytopenia (Grade 3: 5%; Grade 4: 2%). Despite the frequency of neutropenia, there were no episodes of neutropenic fever.
Only 3 patients (5%) required dose reduction to 100 mg and only 1 patient (1.7%) required a second dose reduction to 75 mg, all due to hematologic toxicity. Serious non-hematologic toxicity was very rare.
Efficacy
In the initial cohort, 14 of the first 28 patients were progression free at 12 weeks. Thus, the study met its primary endpoint. A Kaplan-Meier curve of PFS for 59 evaluable patients is shown in Figure 1. The overall PFS at 12 weeks was 57.2% (2-sided 95% CI: 42.4% – 68.8%). The median PFS was 17.9 weeks (2-sided 95% CI: 11.9 – 24.0 weeks).
Figure 1.
Progression-free survival.
The best response by RECIST for 57 evaluable patients is shown in a waterfall plot (Figure 2). There was one complete response lasting over 2 years. Two patients did not have follow-up CT scans on study due to clinical deterioration. There was no significant difference in PFS between patients who had or had not received prior systemic therapy (p = 0.70).
Figure 2.
Waterfall plot showing best tumor response in patients treated with palbociclib.
Discussion
We previously demonstrated that treatment with palbociclib at the 200 mg dose (for 14 days, every 21 days) was associated with favorable progression-free survival and occasional responses in WD/DDLS. The current study confirms those results. Palbociclib was generally well tolerated with asymptomatic reversible neutropenia as the most common side effect. The median PFS at the 125 mg dose was 18 weeks, comparable to the 18 weeks reported in the trial of the 200 mg dose.10 We note that the 125 mg dose has since been FDA approved for breast cancer and is commercially available.
Nine patients in the expansion cohort underwent paired tumor biopsies. The results of these biopsies showed that a clinical benefit from palbociclib treatment was associated with down-regulation of MDM2 mediated by ATRX.13 These data will be crucial to establishing a potential biomarker which could predict which patients may benefit from CDK4 inhibitors.
Acknowledgments
Funding/Support: Palbociclib and partial funding of the clinical trial were supplied by Pfizer. Additional funding was provided by the National Cancer Institute of the National Institutes of Health.
Role of the Funder/Sponsor:
Pfizer had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
This study was funded and study drug was supplied by Pfizer.
This study was supported in part by the National Cancer Institute and the National Institutes of Health through the Soft Tissue Sarcoma Program Project grant P01 CA047179 (S.S, G.K.S., and C.R.A.) and the SPORE in Soft Tissue Sarcoma (P50 CA140146, S.S., W.T., A.K., G.S., L.Q., P.C., and C.R.A.).
Footnotes
Trial Registration: www.clinicaltrials.gov NCT01209598
Partial results from this study were presented at the 2013 Annual Meeting of the American Society for Clinical Oncology and the 2013 Congress of the European Society for Medical Oncology
Conflict of Interest Disclosures: Dr Dickson, Dr Singer and Dr Schwartz acted as consultants for Pfizer.
Drs Dickson, Koff, Singer, Crago and Schwartz have a planned patent on a companion diagnostic for CDK4 inhibitors.
No other disclosures are reported.
Access to Data and Data Analysis: Dr Dickson had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Additional contributions: We thank Marietta Ezeoke for assistance in data collection. (Marietta Ezeoke, BA, Memorial Sloan Kettering Cancer Center. Compensated as a paid employee – research study assistant – at MSKCC)
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