Table 1.
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.