Table. Patterns of Limitations in Randomized Clinical Trials.
| Trial | ClinicalTrials.gov identifier | Drug, indication | Category of limitation |
|---|---|---|---|
| AETHERA | NCT01100502 | Brentuximab vedotin, classical HL after ASCT consolidation | OS advantage not proven Crossover error |
| ALCANZA | NCT01578499 | Brentuximab vedotin, pcALCL, or CD30-expressing mycosis fungoides in patients who received prior therapy | OS advantage not proven Suboptimal control arm |
| ALCYONE | NCT02195479 | Daratumumab, newly diagnosed multiple myeloma in patients who are transplant ineligible | Suboptimal control arm |
| ALEX | NCT02075840 | Alectinib, ALK-positive metastatic NSCLC, first line | OS advantage not proven Crossover error |
| ALFA-0701 | NCT00927498 | Gemtuzumab ozogamicin, previously untreated AML | OS advantage not proven |
| APHINITY | NCT01358877 | Pertuzumab, adjuvant treatment of ERBB2-positive early breast cancer with chemotherapy and trastuzumab | OS advantage not proven |
| ARAMIS | NCT02200614 | Darolutamide, nonmetastatic castration-resistant prostate cancer | Suboptimal control arm |
| ARCHER1050 | NCT01774721 | Dacomitinib, first-line metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations | OS data not mature |
| ARIEL3 | NCT01968213 | Rucaparib, maintenance for recurrent ovarian, fallopian tube, or primary peritoneal cancer, at least 2 prior lines of therapy | OS advantage not proven—planned interim analysisa |
| ASCEND-4 | NCT01828099 | Ceritinib, metastatic ALK-positive NSCLC | OS advantage not proven Suboptimal control arm |
| AUGMENT | NCT01938001 | Lenalidomide, follicular lymphoma and marginal zone, previously treated (with rituximab) | Suboptimal control arm Crossover error |
| AURA3 | NCT02151981 | Osimertinib, metastatic EGFR T790M-mutated NSCLC after progression | OS data not mature |
| AURELIA | NCT00976911 | Bevacizumab, platinum-resistant, recurrent ovarian cancer with paclitaxel and liposomal doxorubicin | OS advantage not proven Crossover error |
| BFORE | NCT02130557 | Bosutinib, first-line chronic-phase CML | OS advantage not proven Suboptimal control arm Crossover error |
| BRIGHT AML 1003 | NCT01546038 | Glasdegib, newly diagnosed AML in 75 or older or who have comorbidities | Suboptimal control arm |
| CABOSUN | NCT01835158 | Cabozantinib, first-line RCC, intermediate and poor risk | OS advantage not proven |
| CASTOR | NCT02136134 | Daratumumab, myeloma after at least 1 prior therapy | OS data not mature |
| CheckMate 037 | NCT01721746 | Nivolumab, unresectable or metastatic melanoma and disease progression following ipilimumab | OS advantage not proven |
| CheckMate 069 | NCT01927419 | Nivolumab and ipilimumab, BRAF V600 wild-type unresectable or metastatic melanoma | Exploratory analysis OS advantage not proven |
| CheckMate 214 | NCT02231749 | Nivolumab and ipilimumab, first-line intermediate or poor-risk RCC | Crossover error |
| CheckMate 238 | NCT02388906 | Nivolumab, adjuvant melanoma with lymph nodes | Crossover error |
| CLARINET | NCT00353496 | Lanreotide, unresectable or metastatic GEP-NETs, nonfunctional | OS advantage not proven Suboptimal control arm Crossover error |
| CLL14 | NCT02242942 | Venetoclax and obinutuzumab, previously untreated CLL with comorbidities | OS data not mature Suboptimal control arm |
| COLUMBUS | NCT01909453 | Encorafenib and binimetinib, metastatic melanoma with BRAF V600E or V600K mutation | OS data not mature |
| COMPLEMENT 2 | NCT00824265 | Ofatumumab, relapsed CLL | OS advantage not proven Suboptimal control arm |
| DUO | NCT02004522 | Duvelisib, relapsed/refractory CLL or SLL after 2 prior therapies | OS data not mature Suboptimal control arm Crossover error |
| ECHELON-1 | NCT01712490 | Brentuximab vedotin, stage III or IV HL | OS advantage not proven—planned interim analysisa |
| EMBRACA | NCT01945775 | Talazoparib, germline BRCA-mutated ERBB2-negative metastatic breast cancer in patients who have been treated with chemotherapy | OS advantage not proven—planned interim analysisa Suboptimal control arm |
| ENGOT-OV16/NOVA | NCT01847274 | Niraparib, maintenance for recurrent ovarian cancer in CR or PR after platinum-based chemotherapy | OS data not mature |
| ET743-SAR-3007 | NCT01343277 | Trabectedin, unresectable or metastatic liposarcoma or leiomyosarcoma | OS advantage not proven |
| ExteNET | NCT00878709 | Neratinib, adjuvant ERBB2-positive breast cancer | OS advantage not proven |
| GADOLIN | NCT01059630 | Obinutuzumab, follicular lymphoma in patients who relapsed after or are refractory to rituximab | Suboptimal control arm |
| GALLIUM | NCT01332968 | Obinutuzumab, previously untreated stage II bulky, III, or IV follicular lymphoma | OS advantage not proven |
| GOG-0213 | NCT00565851 | Bevacizumab, platinum-sensitive (>6 mo), recurrent ovarian cancer | OS advantage not proven |
| GOG-0218 | NCT00262847 | Bevacizumab, epithelial ovarian, fallopian tube, or primary peritoneal cancer | OS advantage not proven |
| IFM2005-02 | NCT00430365 | Lenalidomide, maintenance for myeloma following ASCT | OS advantage not proven |
| iLLUMINATE | NCT02264574 | Ibrutinib, treatment-naive CLL, in patients aged ≥65 y or <65 y with coexisting conditions | OS data not mature Suboptimal control arm |
| IMpassion130 | NCT02425891 | Atezolizumab, first-line metastatic TNBC | Suboptimal control arm |
| iNNOVATE | NCT02165397 | Ibrutinib, Waldenstrom macroglobulinemia | OS advantage not proven Suboptimal control arm |
| JAVELIN Renal 101 | NCT02684006 | Avelumab, first-line advanced RCC, with axitinib | OS data not mature |
| JGDG | NCT01185964 | Olaratumab, soft tissue sarcoma for which anthracycline is appropriate | Suboptimal control arm |
| KATHERINE | NCT01772472 | TDM-1, adjuvant therapy for ERBB2-positive early breast cancer in patients who previously received trastuzumab and taxane neoadjuvantly with residual disease | OS data not mature |
| KEYNOTE-006 | NCT01866319 | Pembrolizumab, unresectable or metastatic melanoma | Crossover error |
| KEYNOTE-042 | NCT02220894 | Pembrolizumab, first-line NSCLC (PD-L1 ≥1%) | Crossover error |
| KEYNOTE-045 | NCT02256436 | Pembrolizumab, metastatic urothelial carcinoma who progress on platinum therapy | Suboptimal control arm |
| KEYNOTE-054 | NCT02362594 | Pembrolizumab, adjuvant melanoma after complete resection | OS data not mature Suboptimal control arm |
| MAIA | NCT02252172 | Daratumumab, newly diagnosed multiple myeloma that are transplant ineligible | OS data not mature Suboptimal control arm Crossover error |
| METEOR | NCT01865747 | Cabozantinib, advanced RCC in following 1 line of therapy | Suboptimal control arm |
| MONALEESA-2 | NCT01958021 | Ribociclib, postmenopausal HR-positive, ERBB2-negative breast cancer, first line | OS data not mature |
| MONARCH 3 | NCT02246621 | Abemaciclib, postmenopausal HR-positive, ERBB2-negative breast cancer | OS data not mature |
| Motzer et al, 2015 | NCT01136733 | Lenvatinib plus everolimus, advanced RCC following 1 line of therapy | OS advantage not proven |
| MURANO | NCT02005471 | Venetoclax, CLL with or without 17p deletion, in patients who received at least 1 line of therapy | Suboptimal control arm |
| OCEANS | NCT00434642 | Bevacizumab, platinum-sensitive (>6 mo), recurrent ovarian cancer | OS advantage not proven |
| OlympiAD | NCT02000622 | Olaparib, germline BRCA-mutated ERBB2-negative metastatic breast cancer in patients who have been treated with chemotherapy | OS advantage not proven Suboptimal control arm |
| PALOMA-1 | NCT00721409 | Palbociclib, postmenopausal HR-positive, ERBB2-negative breast cancer | OS advantage not proven |
| PALOMA-2 | NCT01740427 | Palbociclib, postmenopausal HR-positive, ERBB2-negative breast cancer | OS data not mature |
| PANORAMA-1 | NCT01023308 | Panobinostat, myeloma after at least 2 lines of therapy | OS advantage not proven |
| POLLUX | NCT02076009 | Daratumumab, myeloma after at least 1 prior therapy | OS data not mature Suboptimal control arm |
| PROLONG | NCT01039376 | Ofatumumab, extended therapy (maintenance) in recurrent/progressive CLL in PR/CR | OS advantage not proven |
| PROSPER | NCT02003924 | Enzalutamide, nonmetastatic castration-resistant prostate cancer | OS advantage not proven—planned interim analysisa Suboptimal control arm |
| RADIANT-4 | NCT01524783 | Everolimus, progressive, nonfunctional gastrointestinal and lung NET | OS data not mature Suboptimal control arm |
| RESONATE | NCT01578707 | Ibrutinib, previously treated CLL | Suboptimal control arm |
| RESONATE-2 | NCT01722487 | Ibrutinib, first-line CLL | Suboptimal control arm |
| RESPONSE | NCT01243944 | Ruxolitinib, polycythemia vera in patients who had inadequate response to hydroxyurea | OS not studied, but desirable Crossover error |
| SELECT | NCT01321554 | Lenvatinib, metastatic differentiated thyroid cancer | OS advantage not proven Crossover error |
| SOLAR-1 | NCT02437318 | Alpelisib, HR-positive, ERBB2-negative, PIK3CA-mutated metastatic breast cancer, postmenopausal women and men | OS data not mature |
| SOLO1 | NCT01844986 | Olaparib, first-line maintenance for BRCA-mutated ovarian cancer in CR or PR after platinum-based chemotherapy | OS advantage not proven—planned interim analysisa Crossover error |
| SOLO2/ENGOT-Ov21 | NCT01874353 | Olaparib, maintenance for relapsed ovarian cancer in CR or PR after platinum-based chemotherapy | OS data not mature |
| SPARTAN | NCT01946204 | Apalutamide, nonmetastatic castration-resistant prostate cancer | OS advantage c—second interim Suboptimal control arm Crossover error |
| S-TRAC | NCT00375674 | Sunitinib, adjuvant RCC | OS advantage not proven |
| Study 0761-010 | NCT01728805 | Mogamulizumab, relapsed or refractory mycosis fungoides or Sezary syndrome after at least 1 prior systemic therapy | OS advantage not proven Suboptimal control arm Crossover error |
| TOURMALINE-MM1 | NCT01564537 | Ixazomib, myeloma after at least 1 prior therapy | OS advantage not proven Suboptimal control arm |
Abbreviations: ALK, anaplastic lymphoma kinase; AML, acute myeloid leukemia; ASCT, autologous stem cell transplant; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CR, complete response; EGFR, epidermal growth factor receptor; GEP-NET, gastroenteropancreatic neuroendocrine tumor; HL, Hodgkin lymphoma; HR, hormone receptor; NSCLC, non–small cell lung cancer; OS, overall survival; pcALCL, primary cutaneous anaplastic large cell lymphoma; PD-L1, programmed cell death ligand 1; PR, partial response; RCC, renal cell carcinoma; SLL, small lymphocytic lymphoma; TDM-1, trastuzumab emtansine; TNBC, triple-negative breast cancer.
a
Refers to specified analysis of OS. These may show an OS advantage in the future.