Cancer Chemother Pharmacol (2015) 76:417–423 DOI 10.1007/s00280-015-2813-9
ORIGINAL ARTICLE
Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum‑sensitive epithelial ovarian, fallopian tube, or peritoneal cancer Ursula Matulonis1 · Suzanne Berlin1 · Hang Lee2 · Christin Whalen1 · Elizabeth Obermayer1 · Richard Penson3 · Joyce Liu1 · Susana Campos1 · Carolyn Krasner3 · Neil Horowitz4
Received: 4 June 2015 / Accepted: 17 June 2015 / Published online: 29 June 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Objectives Combining histone deacetylase inhibitors and chemotherapy is synergistic. This phase I study combined escalating vorinostat doses with constant doses of carboplatin and gemcitabine for the treatment of recurrent platinum-sensitive ovarian cancer. The objectives of this study were to determine the maximally tolerated dose of this combination; secondary objectives included preliminary response rate of this regimen and toxicity profile. Methods Fifteen patients with relapsed ovarian cancer were enrolled into this phase I study. Doses of carboplatin and gemcitabine were AUC 4 on day 1 and 1000 mg/m2 on days 1 and 8, respectively; cycles were administered every 21 days. Vorinostat was tested using four different schedules. The first dose level (DL A) tested vorinostat as daily oral dosing from days 1 to 14. DL B tested twice daily (BID) vorinostat dosing on days 1–3 and 8–10. DL C tested BID vorinostat dosing on days 1, 2, 8, and 9, starting vorinostat 1 day prior to initiation of carboplatin and gemcitabine, and DL D tested vorinostat on days 1 and 2 with chemotherapy starting on day 2. Results All four DLs tested resulted in dose-limiting toxicities, and no MTD was determined. Toxicities were
* Ursula Matulonis [email protected] 1
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA
2
Massachusetts General Hospital Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
3
Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
4
Division of Gynecologic Oncology, Brigham and Women’s Hospital, Boston, MA, USA
mostly hematologic. Seven patients were evaluable for RECIST assessment, and six of them had partial responses (PR) via RECIST. Conclusions Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early. Keywords Ovarian cancer · HDAC inhibitors · Vorinostat · Platinum sensitive
Introduction Ovarian cancer will be diagnosed in 21,980 women in the USA in 2014 [1]; the majority of patients are diagnosed with advanced FIGO stage III or IV cancer and will eventually develop cancer recurrence following initial platinumand taxane-based chemotherapy [2, 3]. Recurrences are defined by the duration of time between receipt of last platinum and evidence of cancer recurrence which is called the platinum-free interval (PFI). Platinum doublets are standard of care for treatment of patients with platinum-sensitive recurrence (>6 month PFI) [4, 5]. Strategies to improve progression-free survival (PFS) of platinum doublets have included addition of agents to chemotherapy and/or used as maintenance following completion of chemotherapy [6, 7]. Preclinical rationale exists for using histone deacetylase (HDAC) inhibition as a therapeutic strategy against ovarian cancer. Vorinostat (suberoylanilide hydroxamic acid or SAHA) is an oral HDAC inhibitor that inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, and HDAC3 (class I) and HDAC6 (class II) [8]. Ovarian
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cancer cell lines treated with vorinostat demonstrated an accumulation of cells in G1 and G2, induced apoptosis, and increased levels of acetylated histones 3 and 4 [9]. In addition, HDAC inhibitors combined with chemotherapy such as platinum agents and paclitaxel resulted in synergy [10–13]. Increased platinum adduct formation of the open DNA configuration facilitated by HDAC inhibition has been proposed as a potential mechanism of action for increased cisplatin-induced cell kill [12, 14]. In addition, HDAC inhibitors disrupt intracellular redox balance inducing apoptosis at G1/S arrest and potentiate platinum response, have antiangiogenic activity, and cause acetylation of other proteins such as transcription factors and tumor suppressors. Despite multiple molecular targets that exist for HDAC inhibitors, single HDAC inhibitors have demonstrated only minimal activity when used to treat patients with recurrent ovarian cancer [12–16]. Vorinostat has been tested as a single agent in recurrent ovarian cancer, and of 27 patients tested in the study, only two patients had a 6-month PFS, and one of these patients also had a partial response [17]. Conclusions drawn from this study included that vorinostat was well tolerated, but had minimal single-agent activity in the recurrent platinum-resistant population of patients. Belinostat, another HDAC inhibitor, also had minimal single-agent activity [18]. This study was a phase I study that dose-escalated oral vorinostat with stable doses of carboplatin and gemcitabine chemotherapy is an FDA-approved regimen for the treatment of recurrent platinum-sensitive ovarian cancer. The rationale for combining vorinostat with chemotherapy for ovarian cancer treatment included the observed in vitro synergy of the combination of HDAC inhibitors and chemotherapy and observed preclinical antiovarian cancer activity. The primary objective of this study was to determine the maximally tolerated dose of the combination of vorinostat, carboplatin, and gemcitabine in patients with recurrent platinum-sensitive epithelial ovarian cancer; secondary objectives included a preliminary response rate and progression-free survival rate.
Methods Patients were enrolled from the gynecologic oncology programs at the Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston MA, and all patients were required to sign a Dana-Farber/Harvard Cancer Center Institutional Review Board-approved informed consent form prior to initiating screening for this study. The study was originally designed as a phase I study with subsequent single-arm phase II study, but because of the toxicities observed, only the phase I was performed, and the phase II was never opened; the phase II trial had planned to
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incorporate vorinostat concurrently with chemotherapy and as maintenance. Eligibility Eligibility for this phase I study included the following: a diagnosis of recurrent epithelial ovarian, fallopian tube or peritoneal cancer of any histology or grade, primary platinum sensitive (defined as a cancer initially platinum sensitive followed by a progression-free interval from first exposure to platinum of ≥6 months), RECIST 1.0 [19] measureable cancer, life expectancy >4 months, 18 years of age or older, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, receipt of a maximum of two prior platinum chemotherapy regimens (one at initial diagnosis and one for recurrence) and one non-platinum chemotherapy regimen in the recurrent setting, normal blood counts and organ function, normal QTc interval (QTc ≤ 470 ms) and no history of QTc, able to take oral medications, and no evidence of active or impending malignant bowel obstruction. Exclusion criteria included receipt of radiation therapy to >25 % of bone marrow-bearing areas and current use of valproic acid (another HDAC inhibitor). Study treatment All dose levels used IV carboplatin AUC 4 plus IV gemcitabine 1000 mg/m2 and, 7 days later, gemcitabine 1000 mg/m2 [20]; dose modifications for chemotherapy were based on the FDA package insert. The vorinostat dose and schedules are given in Table 1; if the vorinostat dose was lowered, the dose was lowered by 100 mg, and in some instances, 1 day of vorinostat dosing was eliminated. Cycles were administered every 21 days. Study design The phase I was designed as a traditional 3 + 3 dose escalation design. Three patients were added to a DL; if one of those three patients developed a dose-limiting toxicity (DLT) during the DLT period (first cycle of treatment), an additional three patients would be added. If none of those additional three patients developed a DLT, the next dose level would be explored. If two out of three or two out of six patients developed a DLT, that dose level was considered the DLT dose and no longer explored, and dose de-escalation then occurred. During the phase I, only the dose of vorinostat was escalated, thereby maintaining the integrity of the FDA-approved carboplatin and gemcitabine regimen. Patients were given a drug diary to complete which was checked by the research nursing staff to insure vorinostat compliancy. Toxicities were assessed by Common Terminology Criteria for Adverse Events version 3.0
Cancer Chemother Pharmacol (2015) 76:417–423
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Table 1 Dose levels and DLTs observed Dose level # pts Vorinostat dose and schedule
Carboplatin dosing Gemcitabine dosing
1A 2A 1B
3 3 3
200 mg qd, days 1–14 AUC 4 on day 1 300 mg qd, days 1–14 AUC 4 on day 1 200 mg BID, days 1–3 and 8–10 AUC 4 on day 1
1C
2
200 mg BID, days 1, 2, 8, and 9
AUC 4 on day 2
1D
3
300 mg, days 1 and 2
AUC 4 on day 2
2D
1
400 mg, days 1 and 2
AUC 4 on day 2
DLT results
1000 mg/m2, days 1 and 8 No DLTs 1000 mg/m2, days 1 and 8 2 DLTs: gr 4 thrombocytopenia (both pts) 1000 mg/m2, days 1 and 8 2 DLTs: gr 4 thrombocytopenia (1 pt) and inability to take >75 % of vorinostat dose because of myelosuppression (1 pt) 1000 mg/m2, days 2 and 9 2 DLTs: gr 4 thrombocytopenia and neutropenia (1 pt) and unmanageable gr 3 fatigue (second pt) 1000 mg/m2, days 2 and 9 No DLTs 1000 mg/m2, days 2 and 9 DLT with gr 4 thrombocytopenia, neutrophils; GIP from advanced cancer and passed away
DLT dose-limiting toxicity, pt patient, GIP gastrointestinal perforation, Gr grade, BID twice daily, AUC area under the curve
(CTCAE v3.0). RECIST 1.0 criteria were used to assess response in all patients. The MTD was defined as the highest dose with no more than one DLT occurring on any dose level. The definition of a DLT-evaluable patient included the following: (1) The patient was not removed from the study during cycle 1 because of disease progression or withdrawal of consent, (2) the patient received carboplatin and the first dose of gemcitabine as per the protocol, (3) the patient demonstrated proof via the pill diary that all doses of vorinostat were taken or attempted to be taken, and (4) the subject was compliant with all study procedures and laboratory measurements. The definition of a DLT was defined by the following criteria and was assessed during cycle 1 only: (1) any CTCAE v3.0 grade 3 or 4 non-hematologic event except manageable gastrointestinal toxicity and fatigue, (2) any of the following hematologic events (excluding neutropenia lasting 10 % of patients or any grade 3 or 4 toxicity (n (% of total)): Total number of treated patients is 15 Toxicity
Grades 1 and Grade 3 (%) Grade 4 (%) Total (%) 2 (%)
Fatigue Nausea Neutrophils Platelets Diarrhea Constipation Hypomagnesemia
12 (80) 13 (87) 3 (20) 1 (6.7) 8 (53) 5 (33) 5 (33)
2 (13) 1 (6.7) 6 (40) 2 (13) 0 0 0
0 0 3 (20) 6 (40) 0 0 0
Leukocyte Anemia Alopecia Allergic Reactions
1 (6.7) 3 (20) 3 (20) 1 (6.7)
2 (13) 0 0 1 (6.7)
0 0 0 0
3 (20) 3 (20) 3 (20) 2 (13)
Bruising Vomiting Neuropathy Phlebitis Pulmonary Embolism
2 (13) 2 (13) 2 (13) 2 (13) 0
0 0 0 0 0
0 0 0 0 1 (6.7)
2 (13) 2 (13) 2 (13) 2 (13) 1 (6.7)
Anorexia
0
1 (6.7)
0
1 (6.7)
14 (93) 14 (93) 12 (80) 9 (60) 8 (53) 5 (33) 5 (33)
because of a non-DLT platelet count of 79,000/µL. The trial was then revised to administer vorinostat in 2-day dosing schedule, and the vorinostat was started 1 day before chemotherapy in an attempt to reduce hematologic toxicity (DL 1C): vorinostat 200 mg BID on days 1,2, 8, and 9. However, despite these changes, two patients experienced DLTs on DL 1C: grade 4 thrombocytopenia and neutropenia, and another patient experienced unmanageable grade 3 fatigue and grade 3 thrombocytopenia (non-DLT toxicity). The fourth change to vorinostat dosing and schedule (DL 1D) consisted of vorinostat 300 mg on days 1 and 2 with chemotherapy given on days 2 and 9; no DLTs were observed and DL 2D dose-escalated vorinostat to 400 mg/ day on days 1 and 2 with chemotherapy given on days 2 and 9. The first patient on this dose level experienced a DLT of grade 4 thrombocytopenia, and the trial was then closed. In addition, this patient developed a grade 5 gastrointestinal perforation (GIP) that was deemed not related to study drugs and was assessed by the investigator as related to cancer progression. Other hematologic toxicities observed in the phase I study included anemia which was reported in 3 out of 15 patients and was either grade 1 or grade 2 (Table 2). Nonhematologic toxicities (Table 2) included fatigue observed in 93 % (14 out of 15 patients) of patients which was mostly grade 2 (Table 2). Nausea was also observed in 93 % of
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patients and also mostly grades 1 and 2. Table 2 lists other toxicities thought related to study drugs and occurred in 10 % or more of patients or any grade 3- or grade 4-related toxicity. Two patients developed an allergic reaction to carboplatin; they continued on study, but received carboplatin successfully as a desensitization infusion. Responses Of the seven patients who were assessable for a response and had completed at least two cycles of chemotherapy, six had a PR; five of these were confirmed PRs, and one was unconfirmed. One patient had stable disease. The other eight patients were not evaluable for cancer response because of experiencing DLT toxicities and removal from protocol (5 patients), two patients withdrew consent prior to completing two cycles of treatment, and one died from GIP as discussed above (Table 3).
Discussion Our results demonstrated that although an active regimen, the combination of carboplatin, gemcitabine, vorinostat was difficult to use to treat platinum-sensitive ovarian cancer because of observed hematologic toxicities. Preclinically, HDAC inhibition as a strategy to treat ovarian cancer is a very attractive one, and combinations of HDAC inhibitors, especially with platinum analogs, demonstrate synergy. The doses, schedules, and sequencing of vorinostat in this study were modified four times, and eventually this study was terminated because of the inability to find a tolerable dosing schedule. In addition, other active biologic agents with acceptable toxicity profiles have been identified that extend progression-free survival and can be used in the maintenance setting [6, 7]. HDAC inhibitors have been combined with chemotherapy, especially platinum, and these combinations have been studied in ovarian cancer as well as other solid malignancies. Vorinostat was added to upfront primary induction chemotherapy for advanced ovarian cancer using the regimen of carboplatin AUC 6 on day 1 and paclitaxel 80 mg/ m2/week, both IV, along with vorinostat 200 mg daily every 28 days [21]. Eighteen patients with advanced ovarian cancer were treated, but the study was terminated early because of three events of GIP [21]. Combined grades 3 and 4 neutropenia and thrombocytopenia were observed in 56.3 and 12.5 % of patient, respectively. In our study, we observed one episode of GIP that was attributed to cancer progression and not study therapy; we also observed a high rate of neutropenia and thrombocytopenia. In another study in advanced lung cancer patients, vorinostat 400 mg/day or placebo was added to carboplatin AUC 6 and paclitaxel
Cancer Chemother Pharmacol (2015) 76:417–423 Table 3 Response rates and reasons for discontinuing study treatment
DL
Pt#
1A
421 # CGV
Best RECIST response
Reasons for coming off study treatment
1 2 3 4 5 6 7 8 9
6 6 6 2 1 1 2 1 1
PR (confirmed) PR (not confirmed) PR (confirmed) SD (not confirmed) Not assessable Not assessable Not assessable Not assessable Not assessable
Completed 6 cycles of study treatment Completed 6 cycles of study treatment Completed 6 cycles of study treatment Removed for PE DLT DLT Withdrew consent DLT DLT
1D
10 11 12 13 14
8 1 8 8 2
PR (confirmed) Not assessable PR (confirmed) PR (confirmed) Not assessable
Cycle 1 DLT and completed 8 cycles of study treatment DLT Completed 8 cycles of study treatment Off for PD after 8 cycles Withdrew consent
2D
15
1
Not assessable
DLT and death from PD
2A
1B
1C
PR partial response, SD stable disease, PD progressive disease, DLT dose-limiting toxicity, PE pulmonary embolism, #CGV number of cycles of carboplatin, gemcitabine, and vorinostat received
200 mg/m2 both IV on day 3 of a 21-day cycle [22]. Grade 4 thrombocytopenia was observed more frequently in the vorinostat arm (18 %) versus the placebo arm (3 %), and this was statistically significant (p = 0.05). The addition of vorinostat did not significantly increase either PFS or OS compared to carboplatin and paclitaxel alone [22]. Combination of vorinostat, cisplatin, and gemcitabine was studied in advanced non-small cell lung cancer; the MTD was found to be vorinostat 400 mg for 10 days, cisplatin 75 mg/ m2, and gemcitabine 1250 mg/m2. A DLT dose was not determined because toxicities were not dose limiting [23]. The most common drug-related grade 3 and grade 4 toxicities observed in this study were thrombocytopenia (19 events) and neutropenia (14 events) [23]. Combination of carboplatin AUC 5 and belinostat 1000 mg/m2 IV daily for days resulted in disappointing clinical activity in patients with platinum-resistant ovarian cancer with a response rate of only 7.4 % [24]. Grade 3 and grade 4 thrombocytopenia and neutropenia were observed in 14.8 and 22.2 %, respectively. In our study, hematologic toxicities were the most common toxicities observed during the dose escalation and accounted for six out of the seven observed DLTs. Of the seven patients who experienced DLTs, five had grade 4 thrombocytopenia. This toxicity was more pronounced compared to the phase I study of carboplatin and gemcitabine as well as the randomized phase III study comparing carboplatin versus carboplatin and gemcitabine [4, 25]; the expected incidence of grade 4 thrombocytopenia of carboplatin and gemcitabine is 5 % [20]. Thrombocytopenia appeared more pronounced when compared to other trials combining vorinostat with various other different
chemotherapies [21, 22, 24]. In our study, an acceptable dosing regimen of combination of carboplatin, gemcitabine, and vorinostat without significant toxicities could not be determined. As expected, RECIST responses were observed in this platinum-sensitive patient population who were being treated with their first platinum-based chemotherapy regimen for recurrence. At the time of this study’s initial design, no effective maintenance therapies had been identified for patients with platinum-sensitive ovarian cancer who had completed platinum-based therapy in an attempt to prolong their PFS. However, since the inception of this study, two biologic agents have been successfully tested in the platinum-sensitive recurrence setting. A randomized double-blinded study of the PARP inhibitor olaparib was tested against placebo in the setting of maintenance therapy after a tumor response to a platinum-based regimen. This study showed a significant improvement of PFS for the entire group, but was especially pronounced in women with germline BRCA mutations who demonstrated a 7.1-month overall improvement in PFS for olaparib compared to placebo [6, 26]. Currently, there are several phase III studies testing the efficacy of PARP inhibitors used as maintenance therapy after completion of platinum-based chemotherapy in the setting of platinum-sensitive recurrent ovarian cancer. Agents that interfere with vascular endothelial growth factor such as bevacizumab have been tested in the maintenance setting; OCEANS is a randomized phase III study comparing carboplatin and gemcitabine versus carboplatin, gemcitabine, and bevacizumab and bevacizumab maintenance in women with first relapsed platinum-sensitive ovarian cancer [7]. The median PFS difference between the two groups was
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12.4 versus 8.4 months, which was statistically significant in favor of the group who received bevacizumab during chemotherapy and maintenance. There were no differences with respect to hematologic toxicities, but grade III hypertension and proteinuria were higher in the bevacizumabcontaining arm [7]. For several reasons including the enhanced toxicities of combining HDAC inhibitors with chemotherapy such as seen in this study and others, the observed lack of activity in the platinum-resistant setting and inability to help reverse platinum resistance, and the development and successful testing of other biologic agents such as PARP inhibitors, HDAC inhibitor combinations with other biologic agents rather than myelosuppressive chemotherapy should be considered. Other agents that could be combined with HDAC inhibitors and that have been tested preclinically or in other cancer types include heat shock protein inhibitors and bortezomib [27, 28]. These combinations could eventually be tested as treatment for ovarian cancer if preclinical experiments demonstrate activity and represent an alternative manner of use of HDAC inhibitors for the treatment of ovarian cancer. Acknowledgments Dr. Matulonis received research funding from Merck for the conduct of this study.
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Cancer Chemother Pharmacol (2015) 76:417–423 8. Richon VM, Garcia-Vargas J, Hardwick JS (2009) Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett 280:201–210 9. Takai N, Kawamata N, Gui D et al (2004) Human ovarian carcinoma cells: histone deacetylase inhibitors exhibit antiproliferative activity and potently induce apoptosis. Cancer 21:2760–2770 10. Sonnemann J, Gange J, Pilz S et al (2006) Comparative evaluation of the treatment efficacy of suberoylanilide hydroxamic acid (SAHA) and paclitaxel in ovarian cancer cell lines and primary ovarian cancer cells from patients. BMC Cancer 6:183 11. Cooper AL, Greenberg VL, Lancaster PS et al (2007) In vitro and in vivo histone deacetylase inhibitor activity with SAHA and paclitaxel in ovarian cancer. Gynecol Oncol 104:596–601 12. Nolan L, Johnson PWM, Ganesan A et al (2008) Will histone deacetylase inhibitors require combination with other agents to fulfill their therapeutic potential? Br J Cancer 99:689–694 13. Kim MS, Blake M, Baek JH et al (2003) Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer Res 63:7291–7300 14. Fantin VR, Richon VM (2007) Mechanisms of resistance to histone deacetylase inhibitors and their therapeutic implications. Clin Cancer Res 13:7237–7242 15. Kelly WK, Marks PA (2005) Drug insight: histone deacety lase inhibitors—development of a new targeted anticancer agent suberoylanilide hydroxamic acid. Nat Clin Prac Oncol 2:150–157 16. Gabrielli B, Warrener R, Burgess A et al (1030) Defining the chemotherapeutic targets of histone deacetylase inhibitors. Ann NY Acad Sci 2004:627–635 17. Modesitt SC, Sill M, Hoffman JS et al (2008) A phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 109:182–186 18. Mackay HJ, Hirte H, Colgan T, Covens A, MacAlpine K, Grenci P et al (2010) Phase II trial of the histone deacetylase inhibitor belinostat in women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) tumors. Eur J Cancer 46:1573–1579 19. Therasse P, Arbuck S et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216 20. FDA package insert for gemcitabine for relapsed ovarian cancer. http://www.gemzar.com. Accessed 22 June 2015 21. Mendevil AA, Micha JP, Brown JV, Rettenmaier MA, Abaid LN et al (2013) Increased incidence of severe gastrointestinal events with first-line paclitaxel, carboplatin, and vorinostat chemotherapy for advanced stage epithelial ovarian, primary peritoneal, and fallopian tube cancer. Int J Gynecol Cancer 23:533–539 22. Ramalingam SS, Maitland ML, Frankel P, Argiris AE, Koczywas M et al (2010) Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non small cell lung cancer. J Clin Oncol 28:56–62 23. Tredaniel J, Descourt R, Moro-Sibilot D, Misset J, Gachard E et al (2009) Vorinostat in combination with gemcitabine and cisplatinum in patients with advanced non-small cell lung cancer: a phase I dose escalation study. J Clin Oncol 27:15s (suppl; abstr 8049) 24. Dizon DS, Blessing JA, Penson RT, Drake RD, Walker JL et al (2012) A phase II of belinostat and carboplatin in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 125:367–371
Cancer Chemother Pharmacol (2015) 76:417–423 25. du Bois A, Luck HJ, Pfisterer J et al (2001) Second line carboplatin and gemcitabine in platinum sensitive ovarian cancer—a dose finding study by the Arbeitgemeinschaft Gynakologische (AGO) ovarian cancer study group. Ann Oncol 12:1115–1120 26. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL et al (2014) Olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 15:852–861
423 27. Konstantinopoulos PA, Wilson AJ, Saskowski J, Wass E, Khabele D (2014) Suberoylanilide hydroxamic acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer. Gynecol Oncol 133:599–606 28. Sato A, Asano T, Ito K, Sumitomo M, Asano T (2011) Suberoylanilide hydroxamic acid (SAHA) combined with bortezomib inhibits renal cancer growth by enhancing histone acetylation and protein ubiquitination synergistically. Br J Urol 109:1258–1268
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ORIGINAL ARTICLE
Phase I study of combination of vorinostat, carboplatin, and gemcitabine in women with recurrent, platinum‑sensitive epithelial ovarian, fallopian tube, or peritoneal cancer Ursula Matulonis1 · Suzanne Berlin1 · Hang Lee2 · Christin Whalen1 · Elizabeth Obermayer1 · Richard Penson3 · Joyce Liu1 · Susana Campos1 · Carolyn Krasner3 · Neil Horowitz4
Received: 4 June 2015 / Accepted: 17 June 2015 / Published online: 29 June 2015 © Springer-Verlag Berlin Heidelberg 2015
Abstract Objectives Combining histone deacetylase inhibitors and chemotherapy is synergistic. This phase I study combined escalating vorinostat doses with constant doses of carboplatin and gemcitabine for the treatment of recurrent platinum-sensitive ovarian cancer. The objectives of this study were to determine the maximally tolerated dose of this combination; secondary objectives included preliminary response rate of this regimen and toxicity profile. Methods Fifteen patients with relapsed ovarian cancer were enrolled into this phase I study. Doses of carboplatin and gemcitabine were AUC 4 on day 1 and 1000 mg/m2 on days 1 and 8, respectively; cycles were administered every 21 days. Vorinostat was tested using four different schedules. The first dose level (DL A) tested vorinostat as daily oral dosing from days 1 to 14. DL B tested twice daily (BID) vorinostat dosing on days 1–3 and 8–10. DL C tested BID vorinostat dosing on days 1, 2, 8, and 9, starting vorinostat 1 day prior to initiation of carboplatin and gemcitabine, and DL D tested vorinostat on days 1 and 2 with chemotherapy starting on day 2. Results All four DLs tested resulted in dose-limiting toxicities, and no MTD was determined. Toxicities were
* Ursula Matulonis [email protected] 1
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, USA
2
Massachusetts General Hospital Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA
3
Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA
4
Division of Gynecologic Oncology, Brigham and Women’s Hospital, Boston, MA, USA
mostly hematologic. Seven patients were evaluable for RECIST assessment, and six of them had partial responses (PR) via RECIST. Conclusions Combination of carboplatin, gemcitabine, and vorinostat has activity in relapsed platinum-sensitive ovarian cancer, but was difficult to combine because of hematologic toxicities in this phase I study. No maximally tolerated dose was found, and the study was terminated early. Keywords Ovarian cancer · HDAC inhibitors · Vorinostat · Platinum sensitive
Introduction Ovarian cancer will be diagnosed in 21,980 women in the USA in 2014 [1]; the majority of patients are diagnosed with advanced FIGO stage III or IV cancer and will eventually develop cancer recurrence following initial platinumand taxane-based chemotherapy [2, 3]. Recurrences are defined by the duration of time between receipt of last platinum and evidence of cancer recurrence which is called the platinum-free interval (PFI). Platinum doublets are standard of care for treatment of patients with platinum-sensitive recurrence (>6 month PFI) [4, 5]. Strategies to improve progression-free survival (PFS) of platinum doublets have included addition of agents to chemotherapy and/or used as maintenance following completion of chemotherapy [6, 7]. Preclinical rationale exists for using histone deacetylase (HDAC) inhibition as a therapeutic strategy against ovarian cancer. Vorinostat (suberoylanilide hydroxamic acid or SAHA) is an oral HDAC inhibitor that inhibits the enzymatic activity of histone deacetylases HDAC1, HDAC2, and HDAC3 (class I) and HDAC6 (class II) [8]. Ovarian
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cancer cell lines treated with vorinostat demonstrated an accumulation of cells in G1 and G2, induced apoptosis, and increased levels of acetylated histones 3 and 4 [9]. In addition, HDAC inhibitors combined with chemotherapy such as platinum agents and paclitaxel resulted in synergy [10–13]. Increased platinum adduct formation of the open DNA configuration facilitated by HDAC inhibition has been proposed as a potential mechanism of action for increased cisplatin-induced cell kill [12, 14]. In addition, HDAC inhibitors disrupt intracellular redox balance inducing apoptosis at G1/S arrest and potentiate platinum response, have antiangiogenic activity, and cause acetylation of other proteins such as transcription factors and tumor suppressors. Despite multiple molecular targets that exist for HDAC inhibitors, single HDAC inhibitors have demonstrated only minimal activity when used to treat patients with recurrent ovarian cancer [12–16]. Vorinostat has been tested as a single agent in recurrent ovarian cancer, and of 27 patients tested in the study, only two patients had a 6-month PFS, and one of these patients also had a partial response [17]. Conclusions drawn from this study included that vorinostat was well tolerated, but had minimal single-agent activity in the recurrent platinum-resistant population of patients. Belinostat, another HDAC inhibitor, also had minimal single-agent activity [18]. This study was a phase I study that dose-escalated oral vorinostat with stable doses of carboplatin and gemcitabine chemotherapy is an FDA-approved regimen for the treatment of recurrent platinum-sensitive ovarian cancer. The rationale for combining vorinostat with chemotherapy for ovarian cancer treatment included the observed in vitro synergy of the combination of HDAC inhibitors and chemotherapy and observed preclinical antiovarian cancer activity. The primary objective of this study was to determine the maximally tolerated dose of the combination of vorinostat, carboplatin, and gemcitabine in patients with recurrent platinum-sensitive epithelial ovarian cancer; secondary objectives included a preliminary response rate and progression-free survival rate.
Methods Patients were enrolled from the gynecologic oncology programs at the Dana-Farber Cancer Institute and Massachusetts General Hospital, both in Boston MA, and all patients were required to sign a Dana-Farber/Harvard Cancer Center Institutional Review Board-approved informed consent form prior to initiating screening for this study. The study was originally designed as a phase I study with subsequent single-arm phase II study, but because of the toxicities observed, only the phase I was performed, and the phase II was never opened; the phase II trial had planned to
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Cancer Chemother Pharmacol (2015) 76:417–423
incorporate vorinostat concurrently with chemotherapy and as maintenance. Eligibility Eligibility for this phase I study included the following: a diagnosis of recurrent epithelial ovarian, fallopian tube or peritoneal cancer of any histology or grade, primary platinum sensitive (defined as a cancer initially platinum sensitive followed by a progression-free interval from first exposure to platinum of ≥6 months), RECIST 1.0 [19] measureable cancer, life expectancy >4 months, 18 years of age or older, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, receipt of a maximum of two prior platinum chemotherapy regimens (one at initial diagnosis and one for recurrence) and one non-platinum chemotherapy regimen in the recurrent setting, normal blood counts and organ function, normal QTc interval (QTc ≤ 470 ms) and no history of QTc, able to take oral medications, and no evidence of active or impending malignant bowel obstruction. Exclusion criteria included receipt of radiation therapy to >25 % of bone marrow-bearing areas and current use of valproic acid (another HDAC inhibitor). Study treatment All dose levels used IV carboplatin AUC 4 plus IV gemcitabine 1000 mg/m2 and, 7 days later, gemcitabine 1000 mg/m2 [20]; dose modifications for chemotherapy were based on the FDA package insert. The vorinostat dose and schedules are given in Table 1; if the vorinostat dose was lowered, the dose was lowered by 100 mg, and in some instances, 1 day of vorinostat dosing was eliminated. Cycles were administered every 21 days. Study design The phase I was designed as a traditional 3 + 3 dose escalation design. Three patients were added to a DL; if one of those three patients developed a dose-limiting toxicity (DLT) during the DLT period (first cycle of treatment), an additional three patients would be added. If none of those additional three patients developed a DLT, the next dose level would be explored. If two out of three or two out of six patients developed a DLT, that dose level was considered the DLT dose and no longer explored, and dose de-escalation then occurred. During the phase I, only the dose of vorinostat was escalated, thereby maintaining the integrity of the FDA-approved carboplatin and gemcitabine regimen. Patients were given a drug diary to complete which was checked by the research nursing staff to insure vorinostat compliancy. Toxicities were assessed by Common Terminology Criteria for Adverse Events version 3.0
Cancer Chemother Pharmacol (2015) 76:417–423
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Table 1 Dose levels and DLTs observed Dose level # pts Vorinostat dose and schedule
Carboplatin dosing Gemcitabine dosing
1A 2A 1B
3 3 3
200 mg qd, days 1–14 AUC 4 on day 1 300 mg qd, days 1–14 AUC 4 on day 1 200 mg BID, days 1–3 and 8–10 AUC 4 on day 1
1C
2
200 mg BID, days 1, 2, 8, and 9
AUC 4 on day 2
1D
3
300 mg, days 1 and 2
AUC 4 on day 2
2D
1
400 mg, days 1 and 2
AUC 4 on day 2
DLT results
1000 mg/m2, days 1 and 8 No DLTs 1000 mg/m2, days 1 and 8 2 DLTs: gr 4 thrombocytopenia (both pts) 1000 mg/m2, days 1 and 8 2 DLTs: gr 4 thrombocytopenia (1 pt) and inability to take >75 % of vorinostat dose because of myelosuppression (1 pt) 1000 mg/m2, days 2 and 9 2 DLTs: gr 4 thrombocytopenia and neutropenia (1 pt) and unmanageable gr 3 fatigue (second pt) 1000 mg/m2, days 2 and 9 No DLTs 1000 mg/m2, days 2 and 9 DLT with gr 4 thrombocytopenia, neutrophils; GIP from advanced cancer and passed away
DLT dose-limiting toxicity, pt patient, GIP gastrointestinal perforation, Gr grade, BID twice daily, AUC area under the curve
(CTCAE v3.0). RECIST 1.0 criteria were used to assess response in all patients. The MTD was defined as the highest dose with no more than one DLT occurring on any dose level. The definition of a DLT-evaluable patient included the following: (1) The patient was not removed from the study during cycle 1 because of disease progression or withdrawal of consent, (2) the patient received carboplatin and the first dose of gemcitabine as per the protocol, (3) the patient demonstrated proof via the pill diary that all doses of vorinostat were taken or attempted to be taken, and (4) the subject was compliant with all study procedures and laboratory measurements. The definition of a DLT was defined by the following criteria and was assessed during cycle 1 only: (1) any CTCAE v3.0 grade 3 or 4 non-hematologic event except manageable gastrointestinal toxicity and fatigue, (2) any of the following hematologic events (excluding neutropenia lasting 10 % of patients or any grade 3 or 4 toxicity (n (% of total)): Total number of treated patients is 15 Toxicity
Grades 1 and Grade 3 (%) Grade 4 (%) Total (%) 2 (%)
Fatigue Nausea Neutrophils Platelets Diarrhea Constipation Hypomagnesemia
12 (80) 13 (87) 3 (20) 1 (6.7) 8 (53) 5 (33) 5 (33)
2 (13) 1 (6.7) 6 (40) 2 (13) 0 0 0
0 0 3 (20) 6 (40) 0 0 0
Leukocyte Anemia Alopecia Allergic Reactions
1 (6.7) 3 (20) 3 (20) 1 (6.7)
2 (13) 0 0 1 (6.7)
0 0 0 0
3 (20) 3 (20) 3 (20) 2 (13)
Bruising Vomiting Neuropathy Phlebitis Pulmonary Embolism
2 (13) 2 (13) 2 (13) 2 (13) 0
0 0 0 0 0
0 0 0 0 1 (6.7)
2 (13) 2 (13) 2 (13) 2 (13) 1 (6.7)
Anorexia
0
1 (6.7)
0
1 (6.7)
14 (93) 14 (93) 12 (80) 9 (60) 8 (53) 5 (33) 5 (33)
because of a non-DLT platelet count of 79,000/µL. The trial was then revised to administer vorinostat in 2-day dosing schedule, and the vorinostat was started 1 day before chemotherapy in an attempt to reduce hematologic toxicity (DL 1C): vorinostat 200 mg BID on days 1,2, 8, and 9. However, despite these changes, two patients experienced DLTs on DL 1C: grade 4 thrombocytopenia and neutropenia, and another patient experienced unmanageable grade 3 fatigue and grade 3 thrombocytopenia (non-DLT toxicity). The fourth change to vorinostat dosing and schedule (DL 1D) consisted of vorinostat 300 mg on days 1 and 2 with chemotherapy given on days 2 and 9; no DLTs were observed and DL 2D dose-escalated vorinostat to 400 mg/ day on days 1 and 2 with chemotherapy given on days 2 and 9. The first patient on this dose level experienced a DLT of grade 4 thrombocytopenia, and the trial was then closed. In addition, this patient developed a grade 5 gastrointestinal perforation (GIP) that was deemed not related to study drugs and was assessed by the investigator as related to cancer progression. Other hematologic toxicities observed in the phase I study included anemia which was reported in 3 out of 15 patients and was either grade 1 or grade 2 (Table 2). Nonhematologic toxicities (Table 2) included fatigue observed in 93 % (14 out of 15 patients) of patients which was mostly grade 2 (Table 2). Nausea was also observed in 93 % of
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patients and also mostly grades 1 and 2. Table 2 lists other toxicities thought related to study drugs and occurred in 10 % or more of patients or any grade 3- or grade 4-related toxicity. Two patients developed an allergic reaction to carboplatin; they continued on study, but received carboplatin successfully as a desensitization infusion. Responses Of the seven patients who were assessable for a response and had completed at least two cycles of chemotherapy, six had a PR; five of these were confirmed PRs, and one was unconfirmed. One patient had stable disease. The other eight patients were not evaluable for cancer response because of experiencing DLT toxicities and removal from protocol (5 patients), two patients withdrew consent prior to completing two cycles of treatment, and one died from GIP as discussed above (Table 3).
Discussion Our results demonstrated that although an active regimen, the combination of carboplatin, gemcitabine, vorinostat was difficult to use to treat platinum-sensitive ovarian cancer because of observed hematologic toxicities. Preclinically, HDAC inhibition as a strategy to treat ovarian cancer is a very attractive one, and combinations of HDAC inhibitors, especially with platinum analogs, demonstrate synergy. The doses, schedules, and sequencing of vorinostat in this study were modified four times, and eventually this study was terminated because of the inability to find a tolerable dosing schedule. In addition, other active biologic agents with acceptable toxicity profiles have been identified that extend progression-free survival and can be used in the maintenance setting [6, 7]. HDAC inhibitors have been combined with chemotherapy, especially platinum, and these combinations have been studied in ovarian cancer as well as other solid malignancies. Vorinostat was added to upfront primary induction chemotherapy for advanced ovarian cancer using the regimen of carboplatin AUC 6 on day 1 and paclitaxel 80 mg/ m2/week, both IV, along with vorinostat 200 mg daily every 28 days [21]. Eighteen patients with advanced ovarian cancer were treated, but the study was terminated early because of three events of GIP [21]. Combined grades 3 and 4 neutropenia and thrombocytopenia were observed in 56.3 and 12.5 % of patient, respectively. In our study, we observed one episode of GIP that was attributed to cancer progression and not study therapy; we also observed a high rate of neutropenia and thrombocytopenia. In another study in advanced lung cancer patients, vorinostat 400 mg/day or placebo was added to carboplatin AUC 6 and paclitaxel
Cancer Chemother Pharmacol (2015) 76:417–423 Table 3 Response rates and reasons for discontinuing study treatment
DL
Pt#
1A
421 # CGV
Best RECIST response
Reasons for coming off study treatment
1 2 3 4 5 6 7 8 9
6 6 6 2 1 1 2 1 1
PR (confirmed) PR (not confirmed) PR (confirmed) SD (not confirmed) Not assessable Not assessable Not assessable Not assessable Not assessable
Completed 6 cycles of study treatment Completed 6 cycles of study treatment Completed 6 cycles of study treatment Removed for PE DLT DLT Withdrew consent DLT DLT
1D
10 11 12 13 14
8 1 8 8 2
PR (confirmed) Not assessable PR (confirmed) PR (confirmed) Not assessable
Cycle 1 DLT and completed 8 cycles of study treatment DLT Completed 8 cycles of study treatment Off for PD after 8 cycles Withdrew consent
2D
15
1
Not assessable
DLT and death from PD
2A
1B
1C
PR partial response, SD stable disease, PD progressive disease, DLT dose-limiting toxicity, PE pulmonary embolism, #CGV number of cycles of carboplatin, gemcitabine, and vorinostat received
200 mg/m2 both IV on day 3 of a 21-day cycle [22]. Grade 4 thrombocytopenia was observed more frequently in the vorinostat arm (18 %) versus the placebo arm (3 %), and this was statistically significant (p = 0.05). The addition of vorinostat did not significantly increase either PFS or OS compared to carboplatin and paclitaxel alone [22]. Combination of vorinostat, cisplatin, and gemcitabine was studied in advanced non-small cell lung cancer; the MTD was found to be vorinostat 400 mg for 10 days, cisplatin 75 mg/ m2, and gemcitabine 1250 mg/m2. A DLT dose was not determined because toxicities were not dose limiting [23]. The most common drug-related grade 3 and grade 4 toxicities observed in this study were thrombocytopenia (19 events) and neutropenia (14 events) [23]. Combination of carboplatin AUC 5 and belinostat 1000 mg/m2 IV daily for days resulted in disappointing clinical activity in patients with platinum-resistant ovarian cancer with a response rate of only 7.4 % [24]. Grade 3 and grade 4 thrombocytopenia and neutropenia were observed in 14.8 and 22.2 %, respectively. In our study, hematologic toxicities were the most common toxicities observed during the dose escalation and accounted for six out of the seven observed DLTs. Of the seven patients who experienced DLTs, five had grade 4 thrombocytopenia. This toxicity was more pronounced compared to the phase I study of carboplatin and gemcitabine as well as the randomized phase III study comparing carboplatin versus carboplatin and gemcitabine [4, 25]; the expected incidence of grade 4 thrombocytopenia of carboplatin and gemcitabine is 5 % [20]. Thrombocytopenia appeared more pronounced when compared to other trials combining vorinostat with various other different
chemotherapies [21, 22, 24]. In our study, an acceptable dosing regimen of combination of carboplatin, gemcitabine, and vorinostat without significant toxicities could not be determined. As expected, RECIST responses were observed in this platinum-sensitive patient population who were being treated with their first platinum-based chemotherapy regimen for recurrence. At the time of this study’s initial design, no effective maintenance therapies had been identified for patients with platinum-sensitive ovarian cancer who had completed platinum-based therapy in an attempt to prolong their PFS. However, since the inception of this study, two biologic agents have been successfully tested in the platinum-sensitive recurrence setting. A randomized double-blinded study of the PARP inhibitor olaparib was tested against placebo in the setting of maintenance therapy after a tumor response to a platinum-based regimen. This study showed a significant improvement of PFS for the entire group, but was especially pronounced in women with germline BRCA mutations who demonstrated a 7.1-month overall improvement in PFS for olaparib compared to placebo [6, 26]. Currently, there are several phase III studies testing the efficacy of PARP inhibitors used as maintenance therapy after completion of platinum-based chemotherapy in the setting of platinum-sensitive recurrent ovarian cancer. Agents that interfere with vascular endothelial growth factor such as bevacizumab have been tested in the maintenance setting; OCEANS is a randomized phase III study comparing carboplatin and gemcitabine versus carboplatin, gemcitabine, and bevacizumab and bevacizumab maintenance in women with first relapsed platinum-sensitive ovarian cancer [7]. The median PFS difference between the two groups was
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422
12.4 versus 8.4 months, which was statistically significant in favor of the group who received bevacizumab during chemotherapy and maintenance. There were no differences with respect to hematologic toxicities, but grade III hypertension and proteinuria were higher in the bevacizumabcontaining arm [7]. For several reasons including the enhanced toxicities of combining HDAC inhibitors with chemotherapy such as seen in this study and others, the observed lack of activity in the platinum-resistant setting and inability to help reverse platinum resistance, and the development and successful testing of other biologic agents such as PARP inhibitors, HDAC inhibitor combinations with other biologic agents rather than myelosuppressive chemotherapy should be considered. Other agents that could be combined with HDAC inhibitors and that have been tested preclinically or in other cancer types include heat shock protein inhibitors and bortezomib [27, 28]. These combinations could eventually be tested as treatment for ovarian cancer if preclinical experiments demonstrate activity and represent an alternative manner of use of HDAC inhibitors for the treatment of ovarian cancer. Acknowledgments Dr. Matulonis received research funding from Merck for the conduct of this study.
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