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. 2018 Oct 9;39(2):517–560. doi: 10.1002/med.21531

Table 1.

Overview of phase I/II clinical trials in various cancers with established autophagy inhibitors. The table indicates the number of patients, treatment approach, patient outcome and the impact on autophagy activity

Malignancies Patient numbers Treatment Achievement/outcome Autophagic response References
• Non–small‐cell lung cancer 8 HCQ Dose‐limiting toxicity: not determined Maximum dose tolerance: not determined
Outcome: progressive disease median PFS 1.8 mo, median OS 9 mo
Autophagic changes: not determined Goldberg et al, A phase I study of erlotinib and HCQ in advanced non‐small cell lung cancer. J Thorac Oncol. 2012
19 HCQ + erlotinib Dose‐limiting toxicity: none
Maximum dose tolerance: 1000 mg/d
Recommended phase II dose: 1000 mg/d
Outcome: PR, SD, median PFS 2 mo, median OS 10.6 mo
Autophagic changes: not determined
• Colon rectal
• Non–small‐lung cancer
• Ovarian
• Soft tissue Sarcoma
• Renal
• Breast
• Melanoma
• Carcinoid
• Bladder
• Prostate
27 Vorinostat (HDACi) + HCQ Dose‐liming toxicity: 800 mg/d HCQ
Maximum dose tolerance: 600 mg/d HCQ
Outcome prolonged SD, PR
Autophagic changes: no significant changes in AV accumulation at Day 49
IHC revealed increased MAP1LC3B at Day 49
Mahalingam et al, Combined autophagy and HDAC inhibition/Autophagy. 2014
• Melanoma
• Colorectal
• Head and neck
• Breast
• Gastric/esophageal
• Prostate
• Pancreas
• Non–small‐cell lung
• Pheo/adrenocortical
27 Temsirolimus (mTOri) + HCQ Dose‐limiting toxicity: 1200 mg/d HCQ
Maximum dose tolerance: 1200 mg/d HCQ for 3 mo, subsequently lowered to 1000 mg/d HCQ
Outcome: PFS of melanoma patients 3.5 mo, SD, no response
Autophagic changes: with 1200 mg/d HCQ significant AV accumulation at 6 wk, increased AVs with temsirolimus + HCQ compared to single HCQ treatment Rangwala et al, Combined MTOR and autophagy inhibition. Autophagy. 2014
• Non–small‐cell lung cancer
• Head and neck
• Melanoma
• Colon
• Breast
• Liposarcoma
• Esophageal (SCC)
• Brain metastasis
37 Temozolomide + HCQ Dose‐limiting toxicity: none
Maximum dose tolerance: not reached
Recommended Phase II dose: 1200 mg/d
Outcome: melanoma and breast PFS > 4 mo, PR, SD
Autophagic changes: accumulation of AVs at 4 wk Rangwala et al, Phase I trial of HCQ with dose‐intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy. 2014
• Glioblastoma multiforme 16 Radiation therapy + temozolomide + HCQ Dose‐limiting toxicity: 800 mg/d HCQ
Maximum dose tolerance: 600 mg/d HCQ
Autophagic changes: not determined Rosenfeld et al, A phase I/II trial of HCQ in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastomas multiforme. Autophagy. 2014
76 Radiation therapy + temozolomide + HCQ Outcome: median OS 15.6 mo Autophagic changes: increased AVs/cell and LC3‐II/I at 3 wk
• Relapsed/refractory myeloma 25 Bortezomib + HCQ Dose‐limiting toxicity: none
Maximum dose tolerance: 1200 mg/d HCQ
Outcome: VGPR, MR, SD, and immediate progression
Autophagic changes: increased AV and LC3‐II/I conversion (2 and 3 wk after treatment, respectively) Vogl et al, Combined autophagy and proteasome inhibition. Autophagy. 2014
• Metastatic pancreatic adenocarcinoma 20 HCQ Dose‐limiting toxicity: not determined
Maximum dose tolerance: not determined
Outcome: Median PFS 45.6 d, overall survival 69 d
Autophagy changes: inconsistent autophagy inhibition Wolpin et al, Phase II and PD study of autophagy inhibition using HCQ in patients with metastatic pancreatic adenocarcinoma. The Oncologist. 2014
• Pancreatic adenoma 35 HCQ + gemcitabine + surgery Dose‐limiting toxicity: none
Maximum dose tolerance: 1200 mg/d HCQ
Outcome: median DFS 12.0 mo
Autophagic changes: end of treatment 65% of patients showed increased LC3‐II staining, which correlated with improved DSF and OS Boone et al, Safety and biologic response of preoperative autopagy inhibition in combination with Gemcitabine in patients with pancreatic adenocarcinoma. Ann Surg Oncol. 2015
Sarcoma Closed early HCQ + sirolimus Dose‐limiting toxicity: not determined
Maximum dose tolerance: not determined
Outcome: PR, SD, progressive disease, no reduction of tumor volume
Autophagic changes: not determined Chi et al, Double autophagy modulators reduce 2‐deoxyglucose uptake in sarcoma patients. Oncotarget. 2015
• Advanced metastatic BRAF mutant melanoma 11 Debrafenib (BRAFi) + trametinib (MEKi) + HCQ Dose‐limiting toxicity: not determined
Maximum dose tolerance: not determined
Outcome: low rate retinal toxicity
Autophagic changes: not determined Nti et al, Frequent subclinical macular changes in combined BRAF/MEK inhibition with high‐dose HCQ as treatment of advanced metastatic BRAF mutant melanoma. Retina. 2017
Relapsed/refractory multiple myeloma 6 Rapamycin + cyclophosphamide + dexamethasone Dose‐limiting toxicity: none
Maximum dose tolerance: not determined
Outcome: MR, SD
Autophagic changes: not determined Scott et al, Double autophagy stimulation using chemotherapy and mTOR inhibition combined with HCQ for autophagy modulation in patients with relapsed or refractory MM. Haematologica. 2017
HCQ + cyclophosphamide + dexamethasone Dose‐limiting toxicity: 1200 mg/d HCQ
Maximum dose tolerance: not determined
Outcome: PR, SD
Autophagic changes: not determined
18 Rapamycin + HCQ + cyclophosphamide + dexamethasone Dose‐limiting toxicity: 1200 mg/d HCQ
Maximum dose tolerance: 800 mg/d HCQ
Outcome: VGPR, PR, MR, SD, immediate progression, median PFS 8.6 mo, median OS 11.3 mo
Autophagic changes: increased AV counts in 600‐1200 mg/d HCQ

Abbreviations: 3‐MA, 3‐Methyladenine; CQ, chloroquine; HCQ, hydroxychloroquine; AV, autophagic vacuoles; DFS, disease‐free survival; IHC, immunohistochemistry; MR, minor response; OS, overall survival; PFS, progression‐free survival; PR, partial response; SD, stable disease; VGPR, very good partial response.