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. Author manuscript; available in PMC: 2019 Feb 1.
Published in final edited form as: Gynecol Oncol. 2017 Dec 6;148(2):393–402. doi: 10.1016/j.ygyno.2017.11.026

Clinical Trials in Gynecologic Oncology: Past, Present, and Future

Christina M Annunziata 1,*, Elise C Kohn 1
PMCID: PMC5801214  NIHMSID: NIHMS925939  PMID: 29212614

Introduction

The Gynecologic Oncology Group has historically performed ground-breaking, practice-changing clinical trials in women's cancers. The current standard of care for initial treatment of ovarian, endometrial, cervical, and trophoblastic cancers was determined by clinical trials completed within this cooperative group structure. For example, trial GOG-0111 set the standard for combining platinum and taxane chemotherapy in ovarian cancer, and more recently GOG-0240 provided evidence for adding bevacizumab to chemotherapy for women with advanced cervical cancer (1,2). The landscape of clinical trial design has markedly changed in recent decades, with a clear emphasis on streamlining drug development towards specific patient populations and indications for investigational agents. Translational science in gynecologic cancers can set the stage for rapid and efficient introduction of new therapies for our patients. The gynecologic oncology community of researchers and clinicians is well positioned to enter into the new era of drug development, with breakthrough discoveries increasing each year. It is clear that we must incorporate smart clinical trial design to get the right drugs to the right patients expeditiously, so we can continue to improve outcome for women with gynecologic cancers.

Current FDA Guidance in Clinical Trials

The FDA has implemented four programs to improve efficiency of the drug development process. These designations include Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval (https://www.fda.gov/forpatients/approvals/fast/ucm20041766.htm). The purpose of these expedited programs is to facilitate development and expedite review of drugs that treat serious conditions and fill an unmet medical need, with the goal of getting important new drugs to patients earlier. The seriousness of a condition is difficult to define, but is based on whether a drug can have an impact on measures of clinical benefit, such as survival, physical function, or progression of a disease to a more serious condition.

The Fast Track designation is given to products that have the potential to address an unmet clinical need, provide therapy where none exists or that is potentially better than available therapy. A sponsor may request Fast Track designation at any time during drug development, and the Agency must provide a response to the request within 60 days. This designation is based on preliminary measures of efficacy in the serious condition, and must have a well-delineated development plan that addresses an unmet medical need. The plan should evaluate whether the agent has an ability to provide benefit while reducing toxicity, for example, or an ability to provide benefit in patients unresponsive to alternative treatment. Successful Fast Track designation allows early and frequent communication with FDA throughout the drug development process such as for discussion of endpoints, biomarker development, or other aspects of trial design to support drug approval. Additionally, Fast Track designation permits a sponsor to request “rolling review,” whereby completed sections of its biologics license application (BLA) or new drug application (NDA) may be submitted instead of submitting an entire completed application.

For a product to qualify for Breakthrough Therapy, it must hold the promise of demonstrating a substantial improvement over available therapy. This is based on the magnitude of the treatment effect in preliminary clinical studies, which must show an advantage compared to a historical control. For example, rucaparib was granted Breakthrough Therapy designation in April 2015, when clinical data from the ARIEL2 study showed that 65% of patients achieved a RECIST response. This is better than historical control with chemotherapy where response rates are <50% in the third line treatment of women with platinum-sensitive ovarian cancer. The Breakthrough designation allowed the FDA to expedite the review of this drug, and to closely guide the generation of evidence needed to support final approval, which was granted in December 2016. The endpoint must measure an effect on irreversible morbidity or mortality, or on symptoms that represent a serious consequence of the disease process. The FDA defines the most clinically significant endpoint for a cancer indication as overall survival. Endpoints could also include a validated surrogate endpoint, or even a pharmacodynamic biomarker, though these endpoints may not be sufficient in and of themselves for later marketing approval. For example, overall response rate and duration of response may be acceptable surrogates if they are closely linked to improving overall survival with an improvement in quality of life. The Breakthrough Therapy designation permits increased FDA guidance, and is thus more efficient if the drug development program starts in the phase 1 setting. Generally, the FDA recommends a preliminary discussion prior to submission of a Breakthrough Designation Request. Once submitted, a response is provided within 60 days.

Priority Review Designation shortens the review period before FDA takes action on an application to 6 months, from the 10 months under standard review. These applications are chosen on the basis of providing significant improvement to treatment safety or efficacy. Applicants may request priority review, but all applications get assigned a review designation by the Agency. Designation of “priority” does not alter the scientific or medical standard for approval, but does allocate more resources for the review of the benefit:risk assessment in order to shorten the review clock, with the goal of getting safe and effective drugs to patients faster. The Prescription Drug User Fee Act (PDUFA) was first enacted in 1992 in order to collect fees from drug companies applying for approval (www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee). If the data in the application meet the criteria for Priority Review Designation, then the 6-month review period date is set from the time that the initial New Drug Application was completed (www.fda.gov/Drugs/DevelopmentApprovalProcess).

The Accelerated Approval mechanism, enacted in 1992 and modified in 2012, focuses on surrogate endpoints that may be demonstrated earlier than the clinical benefit endpoints used for regular approval. These endpoints could be biomarkers, radiographic images, or other measures that are considered reasonably likely to predict clinical benefit based on supportive scientific evidence. In this setting, reduction of tumor burden is considered reasonably likely to predict a clinical benefit, but can be measured well before learning whether a treatment allows patients to live longer. If considering accelerated approval, post-marketing clinical trials should be underway at the time of approval. These confirmatory trials must have a primary endpoint, such as overall survival, that clearly shows clinical benefit.

Implementing these Strategies

The FDA approved 80 new drug indications for non-hematologic malignancies between 2011-2016 (Table 1). Five of these were for gynecologic cancers. The bevacizumab approval was expanded to include three indications in gynecologic cancers: in combination with chemotherapy for cervical cancer, in combination with chemotherapy for platinum-resistant recurrent ovarian cancer, and combined with platinum-based chemotherapy for platinum-sensitive recurrent ovarian cancer. Two indications were based on clinical trials implemented by the Gynecologic Oncology Group/NRG Oncology. These include GOG-240, for the use of bevacizumab with chemotherapy in advanced cervical cancer; and GOG-213, for the use of bevacizumab with chemotherapy in platinum-sensitive recurrent ovarian cancer (2,3). Olaparib and rucaparib were initially approved for treatment of women with BRCA-mutated ovarian cancer. The first FDA indication for each of these drugs was based on biomarker-positive cancer: olaparib received its first approval for the treatment of women with germline BRCA mutation, with recurrent ovarian cancer after 3 or more lines of therapy; rucaparib was approved for the treatment of women with deleterious BRCA mutation (germline or somatic) associated advanced ovarian cancer who have been treated with 2 or more prior regimens.

Table 1. A.

Year Drug Combination Indication Approval Type Other Status Endpoint #Patients Biomarker
2016 rucaparib ovarian cancer accelerated BT, PR, OD ORR, DOR 106 BRCA
2016 crizotinib NSCLC BT, PR ORR, DOR 50 ROS1
2016 palbociclib fulvestrant breast cancer PR, BT PFS 521 ER/PR+, HER2 neg
2016 pembrolizumab NSCLC regular* BT, PR PFS, OS 1338 PD-L1
2016 olaratumab doxorubicin soft tissue sarcoma accelerated FT, BT, PR OS 133
2016 atezolizumab urothelial carcinoma accelerated BT, PR ORR, DOR 310
2016 lenvatinib everolimus renal cell carcinoma PFS 153
2016 everolimus NET - GI or lung PFS 302
2016 nivolumab head and neck (SCCHN) OS 361
2016 cabozantinib renal cell carcinoma BT, FT, PR PFS 375
2016 eribulin liposarcoma PR OS 446
2016 atezolizumab NSCLC OS 1137
2016 bevacizumab carboplatin, paclitaxel, gemcitabine ovarian cancer, platinum-sensitive OS 1157
2015 pembrolizumab NSCLC accelerated ORR 61 PD-L1
2015 nivolumab ipilimumab melanoma accelerated PFS, ORR 142 BRAF V600 wild-type
2015 palbociclib letrozole breast cancer accelerated BT PFS 165 ER/PR +, HER2 neg
2015 alectinib NSCLC accelerated BT, PR ORR, DOR 225 ALK
2015 osimertinib NSCLC accelerated BT ORR 411 EGFR T790M
2015 gefitinib NSCLC ORR 106 EGFR (L858R; delexon 19)
2015 cobimetinib vemurafenib melanoma PFS, OS 495 BRAF V600E or V600K
2015 trametinib dabrafenib melanoma OS 1127 BRAF V600E or V600K
2015 dinutuximab GM-CSF, IL-2, and RA neuroblastoma EFS, OS 226
2015 sonidegib basal cell carcinoma ORR 230
2015 nivolumab NSCLC -squamous OS 272
2015 lenvatinib thyroid cancer PFS 392
2015 nivolumab renal cell carcinoma BT, FT, PR 410
2015 irinotecan liposome 5FU + LV pancreas OS 417
2015 talimogene melanoma ORR 436
2015 trabectedin liposarcoma or leiomyosarcoma PFS 518
2015 nivolumab NSCLC OS 582
2015 trifluridine/tipiracil colorectal cancer OS 800
2015 ipilimumab melanoma RFS 951
2015 ramucirumab FOLFIRI colorectal cancer OS 1072
2015 necitumumab gem/cis NSCLC -squamous OS 1093
2014 trametinib dabrafenib melanoma accelerated ORR, DOR 162 BRAF V600E or V600K
2014 ceritinib NSCLC accelerated ORR, DOR 163 ALK
2014 olaparib ovarian cancer ORR 137 BRCA
2014 nivolumab melanoma accelerated BT ORR, DOR 120
2014 pembrolizumab melanoma accelerated BT ORR 173
201 lanreotide NET - GEP PFS 204
4
2014 ramucirumab gastric or GEJ adenocarcinoma OS 355
2014 bevacizumab paclitaxel, pegylated liposomal doxorubicin, or topotecan ovarian cancer -platinum-resistant PFS 361
2014 bevacizumab Paclitaxel and cisplatin or paclitaxel and topotecan cervical cancer OS 452
2014 ramucirumab paclitaxel gastric or GEJ adenocarcinoma OS 665
2014 ramucirumab docetaxel NSCLC OS 1253
2013 erlotinib NSCLC PFS 174 EGFR (L858R or del exon 19)
2013 afatinib NSCLC PFS 345 EGFR (L858R or del exon 19)
2013 crizotinib NSCLC regular* PFS, ORR 347 ALK
2013 pertuzumab trastuzumab and docetaxel breast cancer pCR 417 HER2
2013 ado-trastuzumab emtansine breast cancer PFS, OS 991 HER2
2013 Ibrutinib mantle cell lymphoma ORR 111
2013 lenalidomide mantle cell lymphoma ORR, DOR 134
2013 denosumab giant cell tumor of bone ORR 304
2013 sorafenib thyroid carcinoma PFS 417
2013 Ra 223 dichloride prostate cancer OS 809
2013 bevacizumab FOLFIRI or FOLFOX colorectal cancer OS 820
2013 Abraxane gemcitabine pancreas OS 861
201 everolimus astrocytoma accelerate ORR 28 TSC
2 d
2012 everolimus renal angiomyolipoma ORR, DOR 118 TSC
2012 imatinib GIST regular* OS 397 KIT
2012 everolimus breast cancer PFS 724 ER/PR+, HER2 neg
2012 pertuzumab trastuzum ab + docetaxel breast cancer PFS 808 HER2
2012 cetuximab FOLFIRI colorectal cancer OS 1210 KRAS mutatio n negative
2012 vismodegib basal cell carcinoma ORR 204
2012 cabozantinib thyroid cancer, medullary PFS 330
2012 axitinib renal cell carcinoma PFS 361
2012 pazopanib soft tissue sarcoma PFS 369
2012 regorafenib colorectal cancer OS 760
2012 abraxane carboplatin NSCLC ORR 1052
2012 enzalutamide prostate cancer OS 1199
2012 ziv-aflibercept FOLFIRI colorectal cancer OS 1226
2011 crizotinib NSCLC accelerated ORR 255 ALK
2011 vemurafenib melanoma OS 675 BRAF V600E
2011 sunitinib NET - pancreatic PFS 171
2011 vandetanib thyroid cancer, medullary PFS 331
2011 everolimus NET - pancreatic PFS 410
2011 cetuximab platinum and 5-FU head and neck (SCCHN) OS 442
2011 ipilimumab melanoma OS 676
2011 abiraterone prostate cancer OS 1195
2011 peginterferon alfa-2b melanoma RFS 1256
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*

previously accelerated; BT, breakthrough therapy; PR, priority review; OD, orphan drug; FT, fast track

Recently Completed Gynecologic Oncology Clinical Trials

During the time period 2011-2016, the Gynecologic Oncology Group/NRG Oncology published 58 peer reviewed articles reporting clinical trial results (Table 2) (3, 4-60). Six publications reported phase 3 clinical trial results. One of these led to an FDA-approved indication, for the addition of bevacizumab to chemotherapy in women with advanced cervical cancer. (Of note, GOG-0213 contributed to the 2016 approved indication for bevacizumab with chemotherapy in women with platinum-sensitive ovarian cancer; the publication was released in 2017 (3).) There were 12 phase 1 clinical trials reported, and the remainder were phase 2 studies. At least 15 of these publications concluded that the compound or regimen was tolerable and interpreted as having reasonable clinical activity justifying further investigation. Five of these trials have influenced practice in the gynecologic oncology community, without a change in the FDA labeled indication. For example, GOG-0174 supported the use of pulsed dactinomycin in gestational trophoblastic neoplasia. In addition, the use of bevacizumab is considered acceptable treatment for women with recurrent endometrial cancer (GOG-0229E) and rare ovarian stromal tumors (GOG-0251). Nab-paclitaxel (Abraxane) was added to the armamentarium to treat recurrent ovarian cancer after GOG-0126R. For vulvar cancer, GOG-0205 added the use of weekly cisplatin with radiation. Two agents – veliparib (GOG-0280 and GOG-0077HH) and fosbretabulin (GOG-0186I) moved to the phase 3 setting. Thus, the cooperative group structure has longstanding impact on setting standards for optimal care of women with gynecologic cancer. The improvements come not only from testing new drugs for approval in gynecologic indications, but also for optimizing the use of drugs, with respect to schedule/timing of administration, or combination with other modalities of surgery and radiation.

Table 2. A.

Public
ation
year		 Trial
Number		 Drug Combination Indication Ph
ase		 Endpoint Secondary #
Pati
ents		 Bioma
rker
2016 GOG-0076HH veliparib paclitaxel, cisplatin cervical cancer 1 MTD ORR, PFS, OS 34
2016 GOG-0262 paclitaxel weekly carboplatin +/-bevacizumab ovarian cancer 3 PFS 692
2016 GOG-9927 veliparib carboplatin, doxorubicin, bevacizumab ovarian cancer 1 MTD 39
2016 GOG-0187 paclitaxel ovarian stromal tumors 2 ORR 31
2016 GOG-9925 motolimod pegylated liposomal doxorubicin (PLD) ovarian cancer 1 MTD 297
2016 GOG-0186I fosbretabulin * bevacizumab ovarian cancer 2 PFS ORR 107
2015 GOG-0229H selumetinib endometrial cancer 2 ORR PFS, OS 54
2015 GOG-9920 IP/IV taxol doxorubicin, carboplatin endometrial cancer 1 MTD PFS 21
2015 GOG-0229N dalantercept endometrial cancer 2 T-PFS at 6 mo ORR 28
2015 GOG-0229J cediranib endometrial cancer 2 ORR PFS, OS 53
2015 GOG-0229L trebananib endometrial cancer 2 ORR PFS, OS 32
2015 GOG-0280 veliparib * ovarian cancer 2 PFS OS 50 BRCA
2015 GOG-0250 bevacizumab gemcitabine and docetaxel Uterine leiomyosarcoma 3 OS PFS 107
2015 GOG-0127W veliparib topotecan cervical cancer 2 PFS 27
2014 GOG-0076GG pemetrexed cisplatin cervical cancer 2 ORR PFS, OS 55
2014 GOG-0240 bevacizumab ** cisplatin/paclitaxel or topotecan/paclitaxel cervical cancer 3 OS ORR 452
2014 GOG-0219 tirapazamine cisplatin cervical cancer 3 PFS OS, toleratibily 402
2014 RTOG 0417 bevacizumab cisplatin and radiation cervical cancer 2 OS LRF, PAF, DF, DFS 49
2014 GOG-0251 bevacizumab *** stromal tumors 2 ORR PFS 36
2013 GOG-0239 selumetinib ovarian cancer 2 ORR PFS 52
2014 GOG-0170P Ritolumab (AMG 102) ovarian cancer 2 ORR PFS, OS, AE 31
2014 GOG-0229K nintedanib endometrial cancer 2 EFS AE 37
2014 GOG-0131H ixabepilone recurrent LMS 2 ORR 26
2014 GOG-0248 temsirolimus metformin and tamoxifen endometrial cancer 2 ORR, AE 71
2013 GOG-0229C gefitinib endometrial cancer 2 ORR PFS, AE 29
2013 GOG-0170L Motesanib ovarian cancer 2 ORR PFS, AE 22
2013 GOG-0229G bevacizumab temsirolimus endometrial cancer 2 ORR 53
2012 GOG- Iniparib paclitaxel and carboplatin uterine 2 ORR 22
0232C carcinosarcoma
2012 GOG-0127V nab-paclitaxel cervical cancer 2 ORR, PFS, OS 37
2012 GOG-0229F aflibercept endometrial cancer 2 PFS OS 49
2012 GOG-0126T belinostat carboplatin ovarian cancer 2 ORR PFS, OS 29
2012 GOG-0170G lapatinib ovarian cancer 2 PFS ORR 25
2012 GOG-0170N urokinase-derived peptide (A6) ovarian cancer 2 ORR PFS 31
2012 GOG-9916 docetaxel IP carbo, IP taxol ovarian cancer 1 MTD 40
2012 GOG-0229D lapatinib endometrial cancer 2 PFS ORR 30
2012 GOG-0230B thalidomide Uterine carcinosarcoma 2 ORR PFS, OS 45
2012 GOG-0087M trabectidin uterineleimyosarcoma 2 ORR 20
2012 GOG-0205 cisplatin weekly *** radiation vulvar cancer 2 ORR 58
2012 GOG-9918 cetuximab cisplatin and radiation cervical cancer 1 MTD ORR 64
2012 GOG-9910 p53 vaccine ovarian cancer 2 immune response PFS, OS 21
2012 GOG-9913 topotecan cisplatin and radiation cervical cancer 1 MTD 11
2011 GOG-0227E cetuximab cervical cancer 2 ORR PFS, OS 35
2012 GOG-0170M dasatinib ovarian cancer 2 ORR PFS, OS 34
2011 GOG-0229E bevacizumab *** endometrial cancer 2 PFS, ORR 56
2011 GOG-0170I temsirolimus ovarian cancer 2 PFS ORR 60
2011 GOG-0218 bevacizumab paclitaxel and carboplatin ovarian cancer 3 PFS OS 1873
2011 GOG-0126R nab-paclitaxel *** ovarian cancer 2 ORR PFS 51
2011 GOG-0188 fulvestrant endometrial cancer 2 ORR PFS, OS 67
2011 GOG-9921 intraperitoneal cisplatin and paclitaxel ovarian cancer 1 feasibility 21
2011 GOG-0076DD cetuximab cisplatin cervical cancer 2 ORR 69
2011 GOG-9916 paclitaxel IP carbo, IP taxol ovarian cancer 1 MTD 90
2011 GOG-0146Q topotecan daily *** vs. weekly ovarian cancer 2 PFS OS 80
2011 GOG-9915 docetaxel radiation ovarian cancer 1 ORR PFS 13
2011 GOG-0170F sorafenib ovarian cancer 2 PFS 70
2011 GOG-0186F trabectidin docetaxel ovarian cancer 2 ORR 71
2011 GOG-0174 weekly methotrexate vs. pulsed dactinomycin *** GTN 3 CR 216
2011 GOG-0129Q gemcitabine endometrial cancer 2 ORR PFS 23
2011 GOG-0170J enzastaurin ovarian cancer 2 ORR, PFS OS 27
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*

ongoing phase 3 study;

**

FDA approval;

***

accepted into practice, no FDA label change

Ongoing Clinical Trials in Gynecologic Oncology

Overall, there are 551 clinical trials enrolling women with ovarian cancer, 164 for endometrial cancer, and 230 for cervical cancer listed on clinicaltrials.gov (search date 10/12/2017; terms: ovarian cancer, endometrial cancer, uterine cancer, cervical cancer). Currently, the NRG Oncology cooperative group manages 17 potentially practice-changing clinical trials, with planned accrual of at least 80 patients each, for women with gynecologic malignancies (Table 3). Seven are phase 3 studies, 4 have phase 2/3 design, 2 are randomized phase 2 studies, and 5 are single arm phase 2 studies. The average accrual target per trial is 407 patients (range of 84-1052). The trial size is intentionally smaller than in past decades, with a shift toward the phase 2/3 design, to use information efficiently, and with a larger effect size sought, based on biomarker hypotheses. The rationale for limiting trial size is not simply based on financial constraints. More efficient trial design helps our patients by exposing fewer women to potentially harmful but ineffective drugs, or to placebo controls, and by accelerating approval of effective drugs for wider use in the community.

Table 3. A.

Protocol Number Study Title Phase Accrual Target
GOG-0213 (NCT00565851) A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel (or Gemcitabine) Alone or in Combination with Bevacizumab (NSC #704865, IND #113912) Followed by Bevacizumab and Secondary Cytoreductive Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer. NCI-Supplied Agents: Bevacizumab (NSC #704865, IND #113912) 3 1052
RTOG-0724 (NCT00980954) Phase III Randomized Study of Concurrent Chemotherapy and Pelvic Radiation Therapy with or without Adjuvant Chemotherapy in High-Risk Patients with Early-Stage Cervical Carcinoma Following Radical Hysterectomy 3 285
GOG-0263 (NCT01101541) Randomized Phase III Clinical Trial of Adjuvant Radiation Versus Chemoradiation in Intermediate Risk, Stage I/IIA Cervical Cancer Treated with Initial Radical Hysterectomy and Pelvic Lymphadenectomy 3 534
GOG-0264 (NCT01042522) A Randomized Phase II Trial of Paclitaxel and Carboplatin vs. Bleomycin, Etoposide, and Cisplatin for Newly Diagnosed Advanced Stage and Recurrent Chemonaive Sex Cord-Stromal Tumors of the Ovary 2 128
ANZGOG-0902-GOG-0274 (NCT01414608) A Phase III Trial of Adjuvant Chemotherapy Following Chemoradiation as Primary Treatment for Locally Advanced Cervical Cancer Compared to Chemoradiation Alone: The OUTBACK Trial 3 780
GOG-0270 (NCT01500512) GROningen INternational Study on Sentinel Nodes in Vulvar Cancer (GROINSS-V) II: An Observational Study Other 600
GOG-0277 (NCT01533207) A Phase III Randomized Trial of Gemcitabine (NSC# 613327) Plus Docetaxel (NSC# 628503) Followed by Doxorubicin (NSC# 123127) Versus Observation for Uterus-Limited, High Grade Uterine Leiomyosarcoma 3 216
GOG-0275 (NCT01535053) A Phase III Randomized Trial of Pulse Actinomycin-D Versus Multi-Day Methotrexate for the Treatment of Low-Risk Gestational Trophoblastic Neoplasia 3 384
GOG-0281 (NCT02101788) A Randomized Phase II/III Study to Assess the Efficacy of MEK Inhibitor GSK1120212 in Patients with Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer 2/3 250
GOG-0286B (NCT02065687) A Randomized Phase II/III Study of Paclitaxel/Carboplatin/Metformin (NSC#91485) Versus Paclitaxel/Carboplatin/Placebo as Initial Therapy for Measurable Stage III or IVA, Stage IVB, or Recurrent Endometrial Cancer 2/3 540
NRG-GY003 (NCT02498600) Nivolumab with or without Ipilumumab in treating patients with persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer 2 96
NRG-GY004 (NCT02446600) A Phase III Study Comparing Single-Agent Olaparib or the Combination of Cediranib and Olaparib to Standard Platinum-Based Chemotherapy in Women with Recurrent Platinum-Sensitive Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 3 450
NRG-GY005 (NCT02502266) A Randomized Phase II/III Study of the Combination of Cediranib and Olaparib Compared to Cediranib or Olaparib Alone, or Standard of Care Chemotherapy in Women with Recurrent Platinum-Resistant or -Refractory Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (COCOS) 2/3 680
NRG-GY006 (NCT02466971) A Randomized Phase II Trial of Radiation Therapy and Cisplatin Alone or in Combination with Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer 2 188
NRG-GY007 (NCT02713386) Ruxolitinib phosphate, Paclitaxel, and Carboplatin in Treating Patients with Stage III-IV Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 2 162
NRG-GY008 (NCT02728258) Copanlisib in Treating Patients with Persistent or Recurrent Endometrial Cancer 2 84
NRG-GY009 (NCT02839707) Pegylated Liposomal Doxorubicin hydrochloride with Atezolizumab and/or Bevacizumab in Treating Patients with Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer 2/3 488
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Gynecologic Oncology Clinical Trials in the Future

How can we expedite drug development for gynecologic oncology indications? The pattern of development for several recent drugs suggests a more seamless process is possible for moving promising regimens from early phase clinical trials to FDA approval. Phase 2 or even phase 1 trials have led to accelerated approval, making the drug available to patients while the confirmatory phase 3 study proceeds. One example is the phase 2 study for rucaparib. Its approval was based on the outcome of 106 patients with BRCA mutated in germline or in tumor (somatic), combined from two phase 2 clinical trials (Study 10, NCT01482715 and ARIEL2, NCT01891344). Women with ovarian cancer that had relapsed after 2 or more prior therapies received rucaparib 600mg twice daily, and 54% experienced objective tumor responses. This response rate was considered better than available therapies in the third line setting. While the true overall response rate (ORR) for third-line treatment of ovarian cancer patients with BRCA mutation is unknown, this was considered in the setting of the ORR of 63% reported for the combination of liposomal doxorubicin and carboplatin, when given in an earlier setting (second-line) (61), and has the additional benefit of sparing women from platinum toxicity. Safety data were assessed from 377 patients on these two trials, including women whose tumors did not contain BRCA mutation.

Similarly, the approval for olaparib capsules in 2014 was based on the outcome of 137 women with ovarian cancer and germline BRCA mutation who had received at least 3 prior treatment regimens. The overall response rate of 37% in this population was persuasive when compared to previously reported response rates of <20% after several lines of treatment, in the general population of women with ovarian cancer, unselected by BRCA mutation status. Notably, the FDA approvals for both rucaparib and olaparib specifically considered the responses in the patient population with a BRCA mutation in the germline or tumor tissue. This was justified by strong preclinical and clinical data linking BRCA mutations with increased responsiveness to PARP inhibitors.

As exemplified with PARP inhibitors, endpoints in phase 2 clinical trials are typically those other than overall survival. Instead, phase 2 studies seek a measurable effect that may correlate with clinical benefit. The “surrogate” endpoint should be reasonably likely to predict improved overall survival, when considering the accelerated approval pathway through the FDA. These might include overall response rate (ORR), duration of response (DOR), or a biomarker response linked to survival (such as in the case of cholesterol level and mortality from coronary artery disease). Landmark analyses, such as overall survival at 12 months, or PFS at 6 months, are not considered appropriate from the FDA standpoint of regulatory approval, though these endpoints may be useful to provide preliminary data on whether or not to develop an agent further. For example, GOG-0229N used the landmark of TPFS at 6 months to determine whether dalantercept should be moved forward in endometrial cancer patients (12). The statistical design called for 7 patients to reach the 6 month landmark without progressing or receiving non-protocol therapy. Since only 3 patients reached this landmark, the agent was not developed further. The 6-month TPFS would not have been useful for FDA approval considerations, but contributed to the decision that this was not a promising treatment for women with recurrent or persistent endometrial cancer. Also of note, CA-125 is not reliable as a surrogate in the FDA approval process for drugs treating ovarian cancer, given its variability across patients. ORR is considered the most objective endpoint and thus allowable for single arm trials; DOR should only be used in the setting of a randomized phase 2 trial.

The phase 2/3 trial design could expedite the transition from accelerated approval to regular approval. This design usually includes separate endpoints for the phase 2 and phase 3 parts, in order to maintain adequate power with a relatively small sample size. For example, the phase 2 part may have progression-free survival endpoint for statistical purposes, and the phase 3 would then have overall survival as the primary endpoint. Such a trial could be designed to use the overall survival data from patients in the phase 2 portion for the phase 3 endpoint, improving efficiency in patient accrual numbers without requiring alpha spending.

A challenge to the 2/3 design is the perceived increased time to complete accrual, compared to a straight phase 3 study, since enrollment must be halted in order to assess the phase 2 PFS endpoint. For example, GOG-286B trial of paclitaxel and carboplatin +/- metformin for women with advanced endometrial cancer has enrolled approximately 20 patients per month, but will likely take over 40 months to complete accrual of all 540 patients, due to the pause for interim analysis of progression-free survival between the phase 2 and 3 portions. Because all patients will count towards final OS endpoint, however, only 540 women are needed for adequate power to determine whether metformin added to chemotherapy improves overall survival. In other cases where accelerated approval is sought after the phase 2 part, the drug is available to patients sooner, while the phase 3 part is ongoing for regular FDA approval. It is important to recognize that time may actually be saved in this instance, compared to starting with a phase 2 study, and then developing a second phase 3 clinical trial as an entirely new protocol.

The phase 2/3 design can be tailored when the efficacy of the individual arms in a randomized study is not well estimated, and ineffective arms can be eliminated from the full phase 3 study, improving patient safety and preventing randomization to ineffective treatment regimens. The ongoing study NRG-GY005 for women with platinum-resistant ovarian cancer is designed in this way. The phase 2 portion starts with 4 arms – olaparib, cediranib, olaparib+cediranib, and standard chemotherapy. It is designed to drop one or both single-agent arms for the phase 3 study if progression free survival is below the predefined targets. In contrast to this strategy, GOG-182 enrolled over 4000 women to a randomized phase 3 study without an accurate estimate of expected activity for each of the arms (62). It is possible that if study GOG-182 was instead designed as a phase 2/3 study, with accrual suspension after the phase 2 patients had enrolled, the same conclusion could have been reached with 1740 patients, thus exposing 2572 fewer women to toxic therapy without clear benefit (63). It is highly recommended that endpoints and statistical analysis plan should be discussed with FDA when planning the phase 2/3 design for trials with registration intent.

The development of pembrolizumab took the notion of “seamless” one step further, achieving accelerated approval from expansion cohorts on the phase 1 clinical trial, and for 2 separate indications (64). In 2014, the FDA granted pembrolizumab its first accelerated approval based on an ORR of 24% in 173 patients with metastatic melanoma who had relapsed after ipilumumab treatment. In 2015, a different expansion cohort within the same clinical trial resulted in accelerated approval for non-small cell lung cancer (NSCLC) based on 61 patients with PD-L1 expressing tumors (65). Accelerated approval from the phase 1 setting attains the goal of making drugs available to patients early, with strong preliminary evidence of safety and activity, while the definitive clinical trial proceeds to confirm results and gain full FDA approval.

Biomarker-Driven Clinical Trials

It is striking to note that the highest number of new FDA approved indications during the 2011-2016 time frame was in non-small cell lung cancer (NSCLC), with 15 new approvals. Remarkably, 9 of these are linked to biomarker-selected patients. For example, the ALK genomic rearrangement was instrumental in selecting patients for the approval of alectinib, ceritinib, and crizotinib in NSCLC. Accelerated approvals were more likely with biomarker-selected trials, with 9 of the 13 accelerated approvals for any solid tumor given to biomarker-driven indications, compared to 4 accelerated approvals with no molecular marker. Slightly lower numbers of patients were required for both accelerated and regular approvals in biomarker-selected trials. It should be noted that if the biomarker is infrequent in the population, however, then a larger number of people will be screened in order to enroll sufficient patients carrying the biomarker, something that could slow the trial process. Accelerated approvals in biomarker-driven trials considered an average of 172 patients, while accelerated approvals in non-marker indications had an average of 184 patients. Regular approvals followed a similar trend, with an average of 554 patients considered for biomarker-selected indications, and 585 for non-biomarker indications.

Clinical trials that enroll biomarker selected patients may complete faster and have greater differences thus leading to earlier FDA review. This can more rapidly introduce therapeutic options for patients who have the greatest likelihood of benefit. Such a marker should have strong preliminary evidence – both preclinical and clinical – of statistically predicting the effect of the product under study (66,67). A predictive biomarker is one that identifies patients most likely to respond to a particular therapy. This is distinct from a prognostic marker, that indicates the survival of a patient irrespective of treatment. The predictive biomarker can be used for the selection and/or stratification of patients enrolling on the clinical trial, and must have a validated assay performed in a CLIA-qualified laboratory (68). Examples include somatic or germline BRCA1 or 2 mutation for rucaparib, or PD-L1 expression for pembrolizumab in lung cancer. Each of these clinical trials also gained co-approval for the companion diagnostic used for patient selection. Companion diagnostics are under the purview of Center for Devices and Radiologic Health (CDRH), as they are considered a device required for the safe and effective use of a drug.

Single arm, non-stratified biomarker cohorts have been used for gaining both accelerated and regular approval. In most instances, however, for full regular approval it is necessary to demonstrate that the biomarker-expressing cohort has a better outcome with the product under study compared to a group that does not express the biomarker. In this situation, a stratified trial design is appropriate instead of a single-arm study (69). The stratified design will enroll all patients and stratify to arms based on expression of the biomarker. Patients may all receive the experimental product, or may be randomized to experimental versus standard treatment. The number of patients required for sufficient power to show a difference between groups will depend on the magnitude of the difference expected, as with standard phase 3 trial design. Alternatively, it may be more useful to show that the biomarker-expressing group does better with the product compared to standard therapy. Here, an enrichment design would be implemented. Only patients with biomarker-positive disease are included, and randomized to receive the experimental product or standard treatment. This design is typically used when biomarkers have very strong evidence for selecting patients who will benefit from the product. The SOLO1 and SOLO2 clinical trials are examples of an enrichment design, where only women with BRCA mutation were enrolled, and randomized to olaparib or standard of care (placebo) in the maintenance setting following standard chemotherapy (70). A disadvantage is that there will be no data gathered on potential benefit of the product to patients whose cancer does not express the biomarker, and thus the biomarker will not have direct evidence of clinical utility.

Conclusion

With current trends in clinical trials for gynecologic oncology, it is critical to re-think our approach to clinical trial design in order to maximize efficiency of patient accrual, and make the newest drugs available to patients as early as possible. Clinical trials in today's environment should be smarter and more nimble, with “seamless” transition from early phase to later phase testing. Focused trials with efficient use of clinical data have the highest potential to help our patients in the future. Moving promising agents forward with a biomarker for patient selection is most expedited when the marker has strong preclinical and early clinical evidence that predicts a large margin of increase over best available therapy. There have never been more promising agents, or more detailed scientific inquiry into the field of gynecologic cancers as there is today. It is critical to encourage our physician scientists to lead novel insights into new clinical trials focused on key biological drivers and vulnerabilities in women's cancers, translating from the bench to personalized therapies. Riding the wave of enthusiasm to increase access to clinical trials for our patients, we must learn from the past and embrace the present – better science, smarter data analysis, streamlined FDA communication – so we can continue to give our patients hope for the future.

Highlights.

  • Groundbreaking clinical trials have historically been run through cooperative groups.

  • Recent trial design accelerates approval of new agents from phase 1 or 2 settings.

  • Biomarkers are essential to move research forward expeditiously.

  • Our clinician scientists are well positioned to drive new discoveries to patients.

Acknowledgments

We would like to thank Dr. Sanjeeve Balasubramanian for providing detailed information regarding the FDA approval tracks. This work was prepared as part of our official duties in the National Cancer Institute.

Footnotes

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