Table 4.
Published clinical trials based on autophagy modulation in cancer.
| Study Design/Registry Number | Regimen | Indication/Autophagy Biomarker | Results | Reference |
|---|---|---|---|---|
| Phase II, R, DB, PC N = 70 NCT02333890 |
CQ: 500 mg/d Treatment: 14–29 d, 2–6 weeks before surgery |
Newly diagnosed breast cancer/not assessed | No significant difference in Ki67 index (a proliferation-associated nuclear antigen). | (Arnaout et al., 2019) |
| Phase I/II, OL N = 33 NCT01510119 |
HCQ: 600 mg BID Everolimus:10 mg/d |
Clear-cell renal cell carcinoma (previously treated)/not assessed | PR + SD: 67%; PR: 6%; PFS ≥ 6 m: 45%. The primary endpoint (> 40% 6-month PFS rate) was met. HCQ is a tolerable inhibitor of autophagy. | (Haas et al., 2019) |
| Phase II, Simon’s two-stage design; N = 21 NCT01748500 |
Pantoprazole: 240 mg/3w Docetaxel: 75 mg/m2/3w |
mCRPC/not assessed | PR = 31%; mOS = 15.7 m; median PFS = 5.3 m. Tolerable but clinical activity is insufficient. | (Hansen et al., 2019) |
| Phase Ib/II, Single-arm, OL N = 40 NCT01649947 |
HCQ: 200 mg BID/1–21 Day 1: Paclitaxel: 200 mg/m2 Carboplatin: AUC = 6 Bevacizumab: 15 mg/kg |
mNSCLC/not assessed | ORR = 33% (44% in KRAS positive tumors); SD: 53%; PFS: 3.3 m (6.4 m in KRAS positive tumors). Addition of HCQ is safe and tolerable with a modest improvement in clinical responses. | (Malhotra et al., 2019) |
| Phase I, OL N = 35 NCT01480154 |
HCQ: 200–600 mg BID MK-2206 135 0r 200 mg/w |
Advanced solid tumors/pre-planned autophagy biomarkers are not assessed due to high attrition. | SD: 15%; combination increases HCQ plasma levels. Combination therapy is tolerable but antitumor activity is minimal. |
(Mehnert et al., 2019) |
| Phase 2, R, OL N = 112 NCT01506973 |
HCQ: 600 mg BID Gemcitabine hydrochloride +nab-paclitaxel (GA) with or without |
Pancreatic cancer/not assessed | HCQ: 12 m OS: non-HCQ: 41%; 49%, OS: 11.1 in HCQ; 12.1 in non-HCQ PFS: 5.7 m HCQ; 6.4 m non-HCQ, ORR: 38.2% in HCQ; 21.1% in non-HCQ HCQ did not improve the primary end point of OS but may play a role in the locally advanced setting, where tumor response may permit resection. |
(Karasic et al., 2019) |
| Phase III, OL, R N = 500 NCT03504423 (AVENGER 500 trial) |
CPI-613 + modified FOLFIRINOX (devimistat 500 mg/m2, oxaliplatin 65 mg/m2, irinotecan dose of 120 mg/m2; fluorouracil, 400 mg/m2 (bolus), then 2,400 mg/m2/2 w FOLFIRINOX (oxaliplatin, 85 mg/m2; irinotecan, 180 mg/m2; fluorouracil and leucovorin (same) | Metastatic adenocarcioma of pancreas/mitochondrial SOD2, PDK1-4, PDH, KGDH and CD79a and whole-exome sequencing | Objectives: evaluation of ORR and PFS; tumor response Results are not yet available. |
(Philip et al., 2019) |
| Phase I, OL, cohort N = 14 NCT01687179 |
HCQ: 100–200 mg BID Sirolimus: 2 mg (trough levels between 5 and 15 ng/ml) |
Lymphangioleiomyomatosis/metabolomic profiling of polyamine metabolism 5′-methylthioadenosine and arginine | Upregulation of 5′-methylthioadenosine and arginine in the plasma of patients with LAM | (Tang et al., 2019) |
| Phase I, OL, cohort N = 14 24 w treatment + 24 w observation NCT01687179 |
HCQ: 100–200 mg BID Sirolimus: 2 mg (trough levels between 5 and 15 ng/ml) |
Lymphangioleiomyomatosis/AXL receptor tyrosine kinase, brain-derived neurotrophic factor (BDNF), cathepsin D, epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, insulin, receptor tyrosine protein kinase erbB3, and soluble superoxide dismutase 1 | Only BDNF levels changed significantly. A consistent decrease of BDNF levels in comparison to baseline was observed which was not HCQ dosage-dependent. | (Lamattina et al., 2018) |
| NR, OL N = 30 (healthy) N = 43 (EM) |
None | Endometriosis/LC3B-II | The expression of LC3B-II in ectopic endometrium group was significantly lower than that of its eutopic endometrium group. Down-regulated autophagy of ectopic endometrium in secretory phase may be related to the progression of EMs. | (Li et al., 2018a) |
| Phase I, OL N = 20 NCT01835041 |
CPI-613 (devimistat): 500 mg/m2/d Modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2,400 mg/m2 over 46 h) |
Metastatic pancreatic cancer/not assessed | MTD of CPI-613 = 500 mg/m2 per day. 18 patients treated at MTD, ORR (CR + PR) = 61%. PFS = 9 m; mOS =19 m. Clinical activity requires Phase II validation. |
(Alistar et al., 2017) |
| Phase III, R 1. N = 219 2. N = 234 3. N = 204 NCT00719797 NCT00433927 |
1. TRIBE trial (discovery cohort) FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab 2. FIRE-3 trial (validation cohort) FOLFIRI plus bevacizumab 3. FIRE-3 trial (negative control) FOLFIRI plus cetuximab |
mCRC/12 SNPs in eight autophagy-related genes were examined in this study (autophagy-related protein 13 [ATG13], ATG3, ATG5, ATG8, beclin 1, FIP200, ULK1 and UVRAG | G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grades 2–3 hypertension compared with the A/A genotype. Polymorphisms in autophagy-related FIP200 gene may be predictive of hypertension. |
(Berger et al., 2017) |
| OL, case report N = 2 NCT02271516 |
188Re-liposome (0.42 ± 0.04 mCi/kg) | Recurrent ovarian cancer/Cancer Antigen 125 (CA-125) as a marker of drug-resistance | 188Re-liposome reduces CA-125 levels and improves survival. | (Chang et al., 2017) |
| Phase I, OL, cohort N = 14; 24 w treatment + 24 w observation NCT01687179 |
HCQ: 100–200 mg BID Sirolimus: 2 mg (trough levels between 5 and 15 ng/ml) |
Lymphangioleiomyo-matosis/not assessed | Well tolerated; improvement in lung function at 24 weeks, with a decrease in lung function at the 48-week time point. | (El-Chemaly et al., 2017) |
| Phase I/II, NR, OL N = 12 NCT01023477 |
CQ: 250 mg/w and 500 mg/w × 4w | Breast ductal carcinoma in situ (DCIS)/LC3B positive puncta | Chloroquine reduces PCNA proliferation index in DCIS lesions and inhibits autophagic flux (LC3B positive puncta) | (Espina et al., 2017) |
| Phase I/II OL, R N (ricolinostat) = 15 N (combined) = 57 |
Ricolinostat: Phase I cohorts 1–6: 40, 80, 160, 240, and 360 mg on days 1–5 and 8–12 of each 21-day cycle. Bortezomib: 1.0 mg/m2/1.3 mg/m2. Dexamethasone | Relapsed or refractory multiple myeloma/not assessed | Ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well tolerated, and active. | (Vogl et al., 2017) |
| OL, NR N = 65 |
5-FU based treatment (In vitro and in vivo clinical data with gossypol (AT-101) are linked to clinical data) |
Gastric cancer/APE1 expression | Expression of APE1 is associated with poor survival in gastric cancer patients. AT101, an APE1 inhibitor, may promote chemotherapeutic sensitivity. | (Wei et al., 2016) |
| Phase I, OL, NR N = 20 NCT01023737 |
HCQ: 400 mg/day Vorinostat: 600 mg/day |
mCRC/CTSD and LC3-II in on study-biopsies | SD > 16w: 26%; mPFS 2.8 m; mOS 6.7 m. Improved antitumor immunity (decreased exhausted and regulatory T cells and increased effector phenotype T cells) and reduced tumor autophagy | (Patel et al., 2016) |
| Phase Ib/OL, NR N = 38 NCT01583283 |
Ricolinostat: 40–320 mg/d Lenalidomide: 15–25 mg/d Dexamethasone: 40 mg/w |
Relapsed or refractory multiple myeloma/HDAC6 | DLT: ricolinostat ricolinostat 160 mg BID. The pharmacokinetics of ricolinostat and lenalidomide were not affected by coadministration. ORR:55% | (Yee et al., 2016) |
| Phase I, OL, NR N = 25 |
HCQ: 400 mg/d Sirolimus: 2 mg/d Metronomic chemotherapy |
Stage IV refractory metastatic solid tumors/not assessed | ORR=40%; SD:84% Tumor markers dropped >50%. Progression from PD to PR:2; SD to PR:8 Autophagy is a promising target and warrants further Phase II studies |
(Chi et al., 2015a) |
| Phase II, OL, single arm N = 10 NCT01842594 |
Sirolimus: 1 mg HCQ: 200 mg 2×1/d × 2 w |
Sarcoma/uptake of [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) | An inhibition of glycolysis within the tumors without tumor growth was noted. PR: 6/10; SD:3/10, PD:1/10. |
(Chi et al., 2015b) |
| Phase II, OL N = 19 (evaluable) NCT01206530 |
12 cycles:HCQ: 600 mg BID+ FOLFOX (5-FU (400 mg/m2 bolus, then 2,400 mg/m2 over 46h) + leuco-vorin 200 mg/m2, oxaliplatin 85 mg/m2)/bevacizumab 5 mg/kg, all iv/2 w; after 12 cycles, no oxaliplatin. | Previously untreated mRCR/autophagy biomarkers in PBMC | Autophagy is inhibited in PBMCs. ORR: 52% (CR: 5%, PR: 47%) FOLFOX/bevacizumab + HCQ is an active regimen in mCRC. |
(Loaiza-Bonilla et al., 2015) |
| Phase I/II, OL, NR N = 35 NCT01128296 |
HCQ: 1200 mg/d for 31 d Gemcitabine: 1,500 mg/m2 on days 3 and 17 |
Pancreatic adenocarcinoma/LC3-II in PBMC | No dose-limiting toxicities and no Grade 4/5 events related to treatment. 61% had a decrease in CA19-9. Patients with a >51% increase of LC3-II in PBMC had improvement in PFS (15.03 vs. 6.9 months, p < 0.05) and OS (34.8 vs. 10.8 m, p < 0.05). Preoperative autophagy inhibition with HCQ plus gemcitabine is safe and well tolerated. Surrogate biomarker responses (CA 19-9) and surgical oncologic outcomes were encouraging. | (Boone et al., 2015) |
| Case series, OL, NR N = 5 |
CQ: 250 mg/d Reirradiation |
Recurrent glioblastoma | No CQ related toxicity. 2 PR, 1 SD, 1 PD. Encouraging responses were obtained. | (Bilger et al., 2014) |
| Phase I, OL N = 24 |
Pantoprazole: 80, 160, 240, and 360 mg iv prior to doxorubucin (60 mg/m2) | Solid tumors/not assessed | Pantoprazole 240 mg with doxorubicin 60 mg/m2 every 3 weeks: toxicity was predictable and manageable. | (Brana et al., 2014) |
| Phase I, OL, cohort N = 24 NCT01023737 |
HCQ: 400–800 mg/d (d2–d21) Vorinostat: 400 mg/d (d1–21) |
Advanced solid tumors/AV, lysosomal protease CTSD, CDKN1A | HCQ and VOR stimulate the expression of CTSD and CDKN1A and the accumulation of autophagic vacuoles in PBMC. HCQ addition had no significant impact on the pharmaco-kinetic profile of VOR. 46% had PR or SD for ≥2 cycles. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned | (Mahalingam et al., 2014) |
| Phase Ib/II, OL N = 27 |
HCQ: 1200 mg/d Temsirolimus: 25 mg/w |
Advanced solid tumors and melanoma/AV accumulation in PBMC. | Significant AV accumulation with TEM + HCQ compared with baseline only with 1200 mg cohort. SD = 74%; further studies are warranted. TEM and HCQ: safe and tolerable, modulate autophagy in patients, and have significant antitumor activity. | (Rangwala et al., 2014a) |
| Phase Ib/II, OL N = 40 |
HCQ:1200 mg/d Temozolomide: 150 mg/m2 daily for 7/14 d |
Advanced solid tumors and melanoma/autophagic vacuoles peripheral blood mononuclear cells | PR = 14%; SD: 27% in 22 evaluable patients with advanced melanoma. Prolonged stable disease and responses suggest antitumor activity in melanoma patients. | (Rangwala et al., 2014b) |
| Phase I/II OL N (Phase I) = 16 N (Phase II) = 76 NCT00486603 |
HCQ: 200–800 mg/d Temozolomide: initially before RT-75 mg/m(2); maintenance-150 mg/m(2)/d; 5 d/m for 6 m. RT: 60 Gy in 30 fractions |
Newly diagnosed gliablastoma multiforme/AV and LC3-II | MTD of HCQ: 600 mg/d. 800 mg/d: Grades 3–4 neutropenia and thrombocytopenia; OS 12 m = 70%; OS 18 m = 36%; OS 24 m = 25%. HCQ-induced dose dependent increases in AV and LC3-II in PBMC. Autophagy was not consistently achieved. No significant improvement in overall survival. | (Rosenfeld et al., 2014) |
| Phase Ib/II, OL N = 25 |
HCQ: 1,200 mg/d Bortezomib: 1.3 mg/m2 |
Relapsed/refractory myeloma/AV accumulation and LC3-II in PBMC | Therapy-induced AV accumulation in bone marrow plasma cells. PR = 14%, MR = 14%, SD = 45%; further studies are warranted. | (Vogl et al., 2014) |
| Phase II OL N = 20 NCT01273805 |
HCQ: 800 and 1,200 mg/d Previously treated with other regimens |
Metastatic pancreatic adenocarcinoma (previously treated)/LC3-II in lymphocytes | Analysis of LC3-II showed inconsistent autophagy inhibition. SD: 10%; PFS: 46.5 d; OS: 69 d. Negligible therapeutic efficacy. | (Wolpin et al., 2014) |
| Phase II R, PC, DB N = 73 NCT01894633 |
CQ: 150 mg/d × 4 w WBI (30 Gy in 10 fractions/d over 2 weeks) |
Brain metastases from solid tumors/not assessed | ORR = CLQ-54%; PL-55%. PFS = CLQ-84%; PL-55% CLQ + WBI improved the control of brain metastasis with no increase in toxicity. CLQ did not improve the RR or OS. |
(Rojas-Puentes et al., 2013) |
| Pilot, single cohort N = 20 |
CQ: 250 mg/day × 5 w; started 1 w before WBRT | Newly diagnosed brain metastases from solid tumors | CR = 2; PR = 12; SD = 1 No treatment-related grade ≥ 3 toxicities or treatment interruption due to toxicity. Median/mean OS = 5.7 and 8.9 m |
(Eldredge et al., 2013) |
| Phase Ib/II, OL N = 12 |
2-deoxyglucose (2-DG) 45 mg/kg |
mCRPC/p62 as marker of 2-DG resistance | P62 decreased in 83% and fluorodeoxyglucose uptake decreased in 63% of patients. 2-DG alone or in combination can be used to target tumor metabolism. | (Stein et al., 2010) |
| Phase II, OL N = 30 |
Sorafenib: 400 mg × 2/d | Relapsed or refractory lymphoma/ LC3‐II in PBLs |
ORR: 13%; OS: 16 m. LC3-II levels at baseline were significantly higher in responsive patients than in nonresponsive patients. PBLs: responsive patients: reduction in LC3-II levels; nonresponsive patients: no change. | (Guidetti et al., 2012) |
| Phase I, OL, R N(HCQ) = 27 N(HCQ + Erlotinib) = 19 NCT01026844 |
HCQ: 400–1000 mg/d (escalated) Erlotinib: 150 mg/d |
Advanced NSCLC/not assessed | HCQ with or without erlotinib was safe and well-tolerated. The recommended phase 2 dose: HCQ 1000mg + erlotinib 150mg. | (Goldberg et al., 2012) |
| Phase II, R, DB, PC N = 30 NCT00224978 |
CQ: 150 mg/d Conventional chemotherapy + radiotherapy |
Glioblastoma multiforme | OS = 24m for CQ; 11m for PL Small sample size suggests larger, more definitive studies. |
(Sotelo et al., 2006) |
R, randomized; DB, double-blind; OL, open label; PC, placebo-controlled; MC, multicenter; N, number of patients; d, day; w, week; m, month; RT, Radiotherapy; PL, placebo; HCQ, hydroxychloroquine; CQ, chloroquine; OS, overall survival; ORR, objective response rate; CR, complete response; PR, partial response; MR, minor response; SD, stable disease; PFS, progression-free survival.
mCRPC, metastatic castration-resistant prostate cancer; mNSCLC, metastatic nonsmall cell lung cancer; mCRC, metastatic colorectal cancer; PBMC, peripheral blood mononuclear cells; AV, autophagic vacuole; UVRAG, UV radiation resistance-associated gene protein; FIP200, focal adhesion kinase family interacting protein of 200 kDa; ULK1, unc-51-like kinase 1; CDKN1A, cyclin-dependent kinase inhibitor 1A.