Table 2.
Examples of Sequentially Randomized Trials in Oncology
| Disease (Reference) | N | First Randomization | Eligibility Criteria for Second Randomization | Second Randomization |
|---|---|---|---|---|
| Non–small cell lung cancer (Belani et al., 2003)33 | 401 | Three different schedules/dose-levels of paclitaxel and carboplatin | Adequate response at week 16 | Paclitaxel continuation therapy versus observation |
| Neuroblastoma (Matthay et al., 2009)34 | 379 | Before the last induction cycle, patients were randomized to one of two consolidation options: autologous purged bone marrow transplantation conditioned with myeloblative chemotherapy and total body irradiation versus three cycles of intensive chemotherapy. | Completion of consolidation with absence of disease progression | 13-cis-retinoic acid × 6 cycles versus observation |
| Metastatic prostate cancer (Thall et al., 2007)35 | 150 | One of four chemotherapy regimens (CVD versus KA/VE versus TEC versus TEE) | Nonresponse (evaluated every 8 weeks) | One of the remaining three chemotherapy regimens to which the patient was not already exposed |
| Multiple myeloma (Mateos et al., 2010)36 | 260 | Induction with one of 2 regimens: VMP versus VTP | Completion of six induction cycles | Maintenance therapy with bortezomib + prednisone versus bortezomib + thalidomide |
| Relapsed or refractory aggressive non-Hodgkin B-cell lymphoma (Kuruvilla et al., 2013, and Crump et al., 2014)37,38 | 554 | One of two chemotherapy regimens: GDP versus DHAP | Recovery from autotransplant toxicity and progression-free status at 3 to 5 weeks post-transplant | Maintenance rituximab versus observation |
| Untreated diffuse large B cell lymphoma (Habermann et al., 2006)39 | 632 | Chemotherapy (CHOP) versus chemo-immunotherapy (R-CHOP) | Adequate response | Maintenance rituximab versus observation |
| Relapsed/resistant follicular lymphoma(van Oers et al., 2006)40 | 465 | Chemotherapy (CHOP) versus chemo-immunotherapy (R-CHOP) | Adequate response | Maintenance rituximab versus observation |
| Acute myeloid leukemia (Stone et al., 2001)41 | 388 | GM-CSF versus placebo added to standard induction chemotherapy | Morphologic complete remission and fitness for further therapy | One of two consolidation regimens: cytarabine versus cytarabine + mitoxantrone |
| Multiple myeloma, ongoing as of 2017 (ECOG-1A11 ENDURANCE, NCT01863550) | Target: 756 | Induction with 12 cycles of VRd versus 9 cycles of CRd | No progression on stage 1 therapy | Maintenance lenalidomide for 2 years versus indefinitely |
| Advanced renal cell cancer, ongoing as of 2017 (NCT01217931) | Target: 240 | Pazopanib versus everolimus versus bevacizumab | No response | Randomized between the two agents not yet used |
| CLL (Matutes et al., 2013)42 | 777 | Chlorambucil or fludarabine alone versus with cyclophosphamide | No response, progression, or relapse within 1 year of remission | Protocol-guided chemotherapy regimen versus TRAC assay-guided regimen |
| Locally advanced pancreatic cancer (Hammel et al., 2016)43 | 223 | Gemcitabine alone versus gemcitabine + erlotinib | Progression-free after 4 months | Two months of the same chemotherapy versus capecitabine + 54 Gy radiotherapy |
| Metastatic colorectal cancer (Tournigand et al., 2015)44 | 156 | mFOLFOX7 + bevacizumab versus XELOX2 + bevacizumab | No progression after 3 months | Maintenance bevacizumab versus bevacizumab + erlotinib |
CRd, Carfilzomib, Revlimid (lenalidomide), dexamethasone; CVD, cyclophosphamide, vincristine, dexamethasone; DHAP, dexamethasone, high-dose cytarabine, cisplatin; GDP, gemcitabine, dexamethasone, cisplatin; GM-CSF, granulocyte colony-stimulating factor; KA/VE, ketoconazole + doxorubicin/vinblastine + estramustine; mFOLFOX7, modified folinic acid, fluorouracil, oxaliplatin; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; TEC, paclitaxel, estramustine, carboplatin; TEE, paclitaxel, estramustine, etoposide; TRAC, tumor response to anti-neoplastic compounds; VMP, Velcade (bortezomib), melphalan, prednisone; VRd, Velcade (bortezomib), Revlimid (lenalidomide), dexamethasone; VTP, Velcade (bortezomib), thalidomide, prednisone; XELOX2, biweekly capecitabine (Xeloda), oxaliplatin.