Phase I trial of ribociclib with platinum chemotherapy in ovarian cancer

BACKGROUND New therapeutic combinations to improve outcomes of patients with ovarian cancer are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer. METHODS This phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib, followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS). RESULTS Thirty-five patients were enrolled. Patients had a mean of 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with poly(ADP-ribose) polymerase inhibitors and/or bevacizumab. The MTD was 400 mg. The most common adverse events included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). The overall RR was 79.3%, with a stable disease rate of 18%, resulting in a clinical benefit rate of 96.6%. Median PFS was 11.4 months. RR and PFS did not differ based on the number of lines of prior chemotherapy or prior maintenance therapy. CONCLUSION This work demonstrates that the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease. TRIAL REGISTRATION ClinicalTrials.gov NCT03056833. FUNDING This investigator-initiated trial was supported by Novartis, which provided drugs and funds for trial execution.


Abstract:
Background: New therapeutic combinations to improve the outcome of ovarian cancer patients are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer.
Methods: This phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS). Results: Thirty-five patients were enrolled. Patients had a mean 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with Poly (ADP-ribose) polymerase inhibitors (PARPi) and/or Bevacizumab. The MTD was 400mg. The most common AEs included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). Overall RR was 79.3% with a stable disease (SD) rate of 18% resulting in a clinical benefit rate of 96.6%. The PFS was 11.4 months.
RR and PFS did not differ based on number of lines of prior chemotherapy or prior maintenance therapy. Conclusions: This work demonstrates the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease.
Trial registration: ClinicalTrials.gov NCT03056833. Funding: This investigator-initiated trial was supported by Novartis who provided drug and funds for trial execution.

Introduction:
Ovarian cancer is the second most common gynecologic malignancy in the United States and is the eighth most common malignancy among women worldwide. (1,2) In the U.S., ovarian cancer is the deadliest of the gynecologic cancers and was predicted to account for nearly 14,000 deaths in 2020 alone.(1) While improvements have been made in ovarian cancer mortality rates, the 5-year relative survival in the U.S. continues to remain below 50%. (1,3,4) Despite recent successes with new therapeutic agents, the majority of patients will develop progressive disease and require new lines of therapy.
Platinum-based chemotherapy regimens are standard of care for the management of ovarian cancer, both as initial treatment and as treatment of recurrent platinum-sensitive disease (defined as recurrence at or beyond 6 months after receiving platinum therapy). (5,6) Recently, the use of maintenance therapy after treatment with platinum-based chemotherapy has demonstrated promising results. Maintenance therapy with poly-adenosine diphosphate [ADP]-ribose polymerases (PARP) inhibitors has significantly improved progression free survival after completion of platinum-based chemotherapy and has led to improved overall survival in women with deleterious BRCA1 or BRCA2 mutations. (7) The vascular endothelial growth factor targeting antibody, bevacizumab, has also been shown to improve progression-free survival (PFS) when used in the maintenance setting.(7-9) However, critical considerations including cost, tolerability, and availability of genomic testing remain limiting factors in the use of these agents in the maintenance setting. (9)(10)(11)(12)(13)(14)(15) Additionally, optimal treatment of women who progress after maintenance therapy is a critical, unanswered question. Thus, identification of new agents that are effective for the management of ovarian cancer remains essential. CDK4/6 inhibitors are a class of novel therapeutics that have shown potential for use in multiple areas of oncology, including breast cancer, liposarcoma, mantle cell lymphoma, germ cell tumors and non-small cell lung cancer. (16)(17)(18)(19)(20)(21) The FDA approved the CDK4/6 inhibitors ribociclib and palbociclib in combination with an aromatase inhibitor for first-line therapy in hormone receptor positive (HR+), HER2 negative breast cancer. (19,21,22) The pharmacologic basis of CDK4/6 inhibitors as an oncologic therapy is based on their ability to halt G1-S progression in the cell cycle.(23) During G1, activation of CDK4 and CDK6 proteins triggers phosphorylation of the retinoblastoma (RB) protein, leading to release of RB-mediated E2F suppression and entry into the S phase.(24) Negative regulation of CDK4 and CDK6 occurs via a combination of proteins, including p16. (23,25) Genomic analyses of the CDK4/6 pathway in ovarian cancer have identified a high percentage of p16 deletions or downregulation, as well as increased mRNA expression of CDK4 and CDK6. (26) These genomic abnormalities can lead to abnormal cellular proliferation, as characterized by cancer cell growth, thus the CDK4/6 pathway represents an appealing therapeutic target in this patient population. Interestingly, pre-clinical studies of the CDK4/6 inhibitor ribociclib in ovarian cancer demonstrated synergistic effects when combined with cisplatin, increasing ovarian cancer cell death. (26) This initially appears paradoxical, as CDK4/6 inhibition blocks the G1-S phase transition and cisplatin works by inducing DNA damage in the S phase. However, the timing of ribociclib administration is critical. Dosing ribociclib concurrently or immediately after cisplatin enhances cisplatin-mediated cell death by prolonging cell cycle arrest in the S/G2/M phase and enhances DNA damage through p-CHK1 and pATR. Additionally, adding ribociclib maintenance after completion of platinum-based therapy delayed cancer cell recovery and growth in vitro and in vivo. (26) This suggested a novel therapeutic strategy that sequences chemotherapy with CDK4/6 inhibition to enhance the efficacy of chemotherapy followed by CDK4/6 inhibitor maintenance to delay recurrence of ovarian cancer. (26) We therefore conducted a phase I trial to test the safety and efficacy of ribociclib (LEE-011) in patients with platinum-sensitive recurrent ovarian cancer. Patient had an average 2.5 prior lines of therapy and over half of the patients received prior maintenance therapy with a PARP inhibitor or bevacizumab. The primary endpoint of this study was to determine the maximum tolerated dose (MTD) of ribociclib (LEE-011) when given concurrently with platinum and taxane chemotherapy. Secondary endpoints included response rates (RR) and progression-free survival. This represents a novel combination of CDK4/6 inhibition with chemotherapy in ovarian cancer and demonstrates the safety and promising efficacy of sequencing this class of drugs with standard of care chemotherapy in ovarian cancer.

Results:
Patient Population: Thirty-five patients were enrolled. Two patients were enrolled in the 200mg ribociclib (LEE-011) dosing group, and 33 patients were enrolled in the 400mg ribociclib (LEE-011) dosing group. Patient characteristics are as described in Table 1 In the 400mg dosing group, 21 patients (62.9%) experienced a grade 3 AE and 10 patients (31.4%) experienced a grade 4 AE. One patient experienced a grade 5 AE possibly related to study drug. This patient experienced a fall at home and did not seek medical treatment for 24hrs and subsequently died. In-depth investigation surrounding this event revealed the patient had adequate blood counts (neutrophil count >1,000, platelet count >100,000) and normal EKG with a normal QTcF interval directly prior to the event therefor it was unlikely due to neutropenic infection, bleeding related to thrombocytopenia or prolonged QTc. Grade 3 and 4 AEs were more common during concurrent chemotherapy (n=33 events) than during maintenance therapy (n=9 events). The most commonly experienced adverse events are described in Table 2. The most common grade 3/4 adverse events were hematologic, including leukopenia (n=19, 54.3%), neutropenia (n=19, 54.3%), lymphopenia (n=8, 22.9%), anemia (n=6, 17.1%), and thrombocytopenia (n=6, 17.1%). However, there was only one occurrence of grade 3/4 febrile neutropenia. Other common adverse events were fatigue, nausea, and hypertension, although grade 3-4 AEs in these categories were rare. Notably, a grade 3-4 prolonged QTcF interval was only experienced by 1 patient.
Efficacy: 29 patients were evaluable for response (4 patients withdrew from the trial prior to first response evaluation via CA125 or CT scan). Nineteen patients (65.5%) demonstrated a partial response (PR) and 4 patients (13.8%) demonstrated a complete response (CR) to therapy. Therefore, the overall response rate was 79.3% (2 patients in 200mg group, 21 patients in 400mg group). When including patients with stable disease (n=5), the overall clinical benefit rate was 96.6% (Table 3). Median PFS was 11.4 months (95% CI 9.10 months to not reached) ( Figure 2).
Among patients who received maintenance therapy, median PFS during the maintenance phase was 9.4 months.
On exploratory analysis, there was no significant difference in PFS between patients who had received prior maintenance PARPi or Bevacizumab therapy compared to those without prior maintenance therapy (median PFS 10.12 months with prior maintenance versus 14.36 months without, p=0.068). CI=(0.77, 1.29), p=0.97). We additionally compared the PFS of patients on trial to their PFS on their most recent therapy prior to trial enrollment. We found that 37% of patients had either improved PFS compared to prior or had not yet progressed. We performed a proportional hazards (Cox) regression on the current trial PFS with prior PFS as a predictor. We found that prior PFS was not significantly associated with current trial PFS (HR 0.9945, 95% CI=(0.96,1.03), p=0.75). Additionally, both prior maintenance therapy (χ 2 test p=0.14) and the number of lines of prior therapy (χ 2 test p=0.31) were not significantly associated with clinical response.
Given the hypothesized resistance to CDK4/6 inhibitors in patients with retinoblastoma tumorsuppressor gene (RB1) mutations, we also sought to correlate responses to RB1 mutational status.
Paraffin-embedded tumor samples were available for 30 patients (86%). RB1 sequencing was performed on all 30 samples. After gene analysis, one patient (3.33%) was found to have a clinically-relevant RB1 mutation, however, her disease was not evaluable for response due to withdrawal from trial.

Discussion:
This phase I trial demonstrates that ribociclib (LEE-011) can be safely administered in the platinum-sensitive ovarian cancer patient population, both sequenced concurrently with platinum and taxane chemotherapy and as maintenance therapy. Ribociclib (LEE-011) was associated with a higher occurrence of grade 3 and 4 hematologic adverse events when sequenced with cytotoxic chemotherapy. However, only one patient experienced grade 3/4 febrile neutropenia.
These safety data are consistent with prior studies of ribociclib. (19,21,27,28) In the MONALEESA-2 trial, ribociclib was administered concurrently with letrozole for patients with advanced or recurrent HR+, HER2 negative breast cancer. (19) In the updated results from that trial, 52.4% and 9.6% of patients experienced grade 3 and 4 neutropenia, and 20.1% and 1. In addition to being safely administered during concurrent therapy, ribociclib (LEE-011) was also well tolerated as maintenance therapy. Only 9 grade 3/4 adverse events occurred on maintenance therapy during this trial, as compared to 33 events during concurrent administration with platinum and taxane chemotherapy. Due to the prolonged time course over which maintenance therapy is typically administered, the tolerability of the maintenance regimen is a key component of use. Advantages of ribociclib (LEE-011) over other maintenance regimens include oral administration and a mechanism of action that is not dependent on BRCA1/BRCA2 or homologous recombination status.
Efficacy was a secondary objective of this study. While it is important not to over-interpret results on small single-institution studies, the efficacy results are encouraging. In the overall cohort, response rate was 79.3% with a clinical benefit rate of 96.6%. Previously reported response rates with platinum-based chemotherapy alone 54-66% and 78.5% with chemotherapy + bevacizumab in the platinum-sensitive recurrent ovarian cancer setting. (9,31) This high RR validates the pre-clinical work which demonstrated a unique synergy with ribociclib sequenced after cisplatin chemotherapy enhancing cisplatin-mediated cytotoxicity (26) . Further, median PFS was 11.4 months. This strong PFS may be a result of both a deepened cytotoxic response with ribociclib plus chemotherapy as well as delayed progression with ribociclib maintenance.
While cross-trial comparisons are fraught, these findings are similar to the OCEANS trial, which was a landmark study assessing the addition of bevacizumab to gemcitabine and carboplatin followed by bevacizumab maintenance in platinum-sensitive recurrent ovarian cancer. The investigators found that the bevacizumab arm had a significantly improved PFS of 12.4 months compared to placebo (PFS of 8.4 months), which is similar to the findings in this trial of ribociclib given concurrently with chemotherapy and as a maintenance regimen. However, in the OCEANS trial, only one prior line of therapy was allowed while the number of prior lines of therapy in this study ranged from 1-8 with an average of 2.4 (with maintenance therapy not included as a line of therapy).(9) Our patient cohort aligns with the expected demographics in epithelial ovarian cancer (largely high grade serous histology, average age of 65 and 17% BRCA1/BRCA2 mutation rate) but was more heavily pretreated than the OCEANS trial cohort.
Overall, our results are highly encouraging and merit further investigation in a larger patient cohort.
Given the paucity of data on treatment response after maintenance therapy in ovarian cancer patients, an exploratory analysis was performed to assess PFS in patients with and without prior maintenance therapy. Interestingly, there was no statistically significant difference in PFS between the groups. On further analysis, there was also no statistically significant association between the number of prior lines of therapy and PFS. Additionally, over 30% of patients had an improved PFS on trial compared to their most recent prior PFS. This is surprising as most patients re-treated with chemotherapy will have reduced benefit with each subsequent therapy (as indicated by a decreased PFS with each successive course of therapy). While not the primary aims of this study, these results suggest that ribociclib may have activity in patients who have received multiple prior lines of chemotherapy or who have previously received another maintenance regimen. This is particularly important, given the ongoing clinical need for treatment approaches for the increasing number of patients that are receiving PARPi or bevacizumab early in their treatment course.
In conclusion, this trial demonstrates that ribociclib (LEE-011) can be safely administered concurrently with chemotherapy in patients with recurrent ovarian cancer. Although safety was the primary objective of this trial, the RR and PFS data suggest substantial activity of ribociclib against ovarian cancer in combination and following platinum-based chemotherapy. This work strongly supports the further investigation of ribociclib (LEE-011) for the treatment of ovarian cancer.

Methods:
This study was a phase I, open-label, single institution dose-escalation trial of ribociclib with platinum-based chemotherapy in recurrent platinum sensitive ovarian cancer (NCT03056833).

Patients
Eligible patients were women of at least 18 years of age with platinum-sensitive recurrent ovarian, fallopian, or primary peritoneal cancer. Platinum-sensitive disease was defined as recurrent disease more than 6 months after completion of the last platinum-based chemotherapy.
All epithelial histologies (high grade serous, endometrioid, clear cell, carcinosarcoma and low grade serous) were included. Patients were recruited from University of Michigan and UPMC cancer clinics. To participate, patients had to be able to provide informed consent and comply with all study protocols. Patients were required to have completed at least 1 prior line of platinum-based therapy, and to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0-1 with a life expectancy of at least 3 months. Disease progression or recurrence was defined by the Gynecologic Cancer InterGroup Response Evaluation Criteria in Solid Tumors (GCIG-RECIST) criteria. (32) Prior to trial enrollment, patients were required to undergo laboratory screening for adequate renal, hepatic, hematologic, and electrolyte parameters, and were required to have a pre-treatment electrocardiogram demonstrating a QTcF interval of less than or equal to 450 msec (using Fridericia's correction).
Patients were excluded based on the following criteria: borderline or low-malignant potential histology, platinum-resistant disease, grade 3 baseline neuropathy, prior use of CDK4/6 inhibitors, congenital long QT syndrome or family history of unexpected sudden cardiac death, clinically significant uncontrolled heart disease or cardiac repolarization abnormalities, history of HIV infection, current pregnancy or lactation, impairment of gastrointestinal function that might alter absorption of the study drugs, or concurrent malignancy or malignancy within 3 years prior to starting the study drug (with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer). Patients were also excluded if they were currently receiving warfarin or other coumadin-derived anticoagulants (low molecular weight heparin and fondaparinux were allowed), currently receiving or had received systemic corticosteroids within 2 weeks of starting the study drug, had major surgery within 14 days prior to starting study drug or had not recovered from major side effects, or had participated in a prior investigational study within 30 days of enrollment or 5 half-lives of the investigational product (whichever was longer).

Study design
The primary endpoint of this study was to determine the maximum tolerated dose of ribociclib (LEE-011) when given with platinum and taxane chemotherapy. Secondary endpoints were response rate and progression-free survival. Dose assignment was determined using the time-toevent continual reassessment method (Figure 1). (33,34) Ribociclib dosing levels were (1) 200mg, (2) 400mg, and (3) 600mg. The target rate for the MTD was set at 0.25 and the standard deviation of the dose-toxicity parameter was assigned a value of 0.1, which was found to work well in simulation studies. The probabilities of DLT at the three dose levels were originally estimated to be 0.1, 0.2 and 0.3, respectively. The trial was originally designed to accrue 40 participants, however, the study was closed to accrual after enrolling 35 patients due to COVID19 limitations and high confidence in the recommended phase II dose (RP2D). Attrition rates and reason for coming off trial was documented for all participants. For the first 15 participants, assignment to a dose level with probability of toxicity 0.05 greater than the target rate was permitted, afterwards, assignment was allowed only to a dose with probability of toxicity less than or equal to the target rate. Ribociclib (LEE-011) dosing was initiated at level 1 (200mg), and dose-escalation was determined for newly enrolled patients based on the TITE-CRM algorithm. The 200mg dose was chosen as the initial starting point for concurrent therapy as ribociclib (LEE-011) has not previously been tested in combination with platinum and taxane chemotherapy. Dose-limiting toxicities were assessed during the first 2 cycles of chemotherapy (first 8 weeks of the study). Safety and toxicity data were followed for the duration of the study (including chemotherapy and maintenance portions).