hydroxychloroquine MDT / VG Lifesciences - LARVOL DELTA

Detection and targeting of minimal residual disease in breast cancer to reduce recurrence: The PENN-SURMOUNT and CLEVER trials (SABCS 2017) - "Contact information: angela.demichele@uphs.upenn.edu Key words: Recurrence, disseminated tumor cells, dormancy, minimal residual disease, autophagy, mTOR, Everolimus, hydroxychloroquine"

Combination therapy • Residual disease • Hormone Receptor Breast Cancer

Targeting autophagy and immunotherapy with hydroxychloroquine and interleukin 2 in patients with metastatic renal cell carcinoma (mRCC): A Cytokine Working Group study. (ASCO-SITC 2018) - P1/2; "Clinical trial information: NCT01550367 Background:The combination of high dose aldesleukin and daily oral HCQ was well tolerated. We have concluded this trial and will report mature survival data, toxicity data, and biomarkers/autophagy measures with the final submission."

Clinical • Renal Cell Carcinoma

Safety and preliminary activity of hydroxychloroquine and aldesleukin in metastatic renal cell carcinoma (mRCC): A cytokine working group study. (ASCO-GU 2017) - P1/2; "Background: Aldesleukin (recombinant human interleukin-2) has been an FDA-approved treatment for mRCC since 1992, based on a 5-10% rate of durable complete remissions. HCQ in combination with aldesleukin was found to be tolerable at a dose of 600 mg daily, with expected toxicities. Clinical responses have been observed."

Renal Cell Carcinoma

Phase II trial of the autophagy inhibitor hydroxychloroquine with FOLFOX and bevacizumab in front line treatment of metastatic colorectal cancer. (ASCO 2017) - P1/2; "The antimalarial agent hydroxychloroquine (HCQ) is a potent inhibitor of autophagy, and in vivo studies in CRC cell models show significant decrease tumor volume when these autophagy inhibitors were combined with oxaliplatin and bevacizumab. These data are promising and further evaluation in a randomized controlled trial is planned."

P2 data • Biosimilar • Colorectal Cancer • Immunology • Venous Thromboembolism

Autophagic cell death with hydroxychloroquine in patients with hormone-dependent prostate-specific antigen progression after local therapy for prostate cancer. (ASCO-GU 2017) - P2; "Hydroxychloroquine appears to have some activity in PSA progression after localized therapy with minimal toxicity. Given that hydroxychloroquine has limited side effects, this drug has the potential to augment responses to hormonal therapy or chemotherapy."

Clinical • Prostate Cancer

Phase II study of autophagy inhibition with hydroxychloroquine (HCQ) and preoperative (preop) short course chemoradiation (SCRT) followed by early surgery for resectable ductal adenocarcinoma of the head of pancreas (PDAC). (ASCO 2017) - P2; "Clinical trial information: NCT01494155 HCQ with preop SCRT and adjuvant gemcitabine-based chemotherapy is well tolerated but did not meaningfully impact DFS. Further pathologic/correlative studies, particularly in outstanding pathologic responders and long term survivors are ongoing."

P2 data • Biosimilar • Immunology • Oncology

Dendritic-cell vaccine (DCVAC) with first-line chemotherapy in patients with stage IV NSCLC: Finalanalysis of phase II, open label, randomized, multicenter trial. (ASCO 2019) - P1/2; " This study evaluated the efficacy and safety of DCVAC/LuCa (active cellular immunotherapy based on dendritic cells) concomitantly added to ct (carboplatin/paclitaxel) - Arm A (A) vs DCVAC/LuCa + immune modulators (IFN-α and hydroxychloroquine) - Arm B (B)+ct vs ct - Arm C (C) in NSCLC patients (pts). Addition of DCVAC-based immunotherapy to the standard of care chemotherapy significantly improved OS in stage IV NSCLC. Clinical trial information: NCT02470468"

Clinical • P2 data

Randomized phase II trial of hydroxychloroquine in combination with gemcitabine/nab-paclitaxel to inhibit autophagy in pancreatic cancer: A SU2C-funded trial (AACR 2018) - "Response rates in patients who received HCQ were higher, and toxicity was tolerable. Autophagy reversal might be explored in the management of locally-advanced disease."

Clinical • Combination therapy • P2 data • Pancreatic Cancer

CHOICES: A RANDOMIZED PHASE II TRIAL FOR IMATINIB VS HYDROXYCHLOROQUINE PLUS IM FOR PATIENTS WITH CML IN MCYR WITH RESIDUAL DISEASE DETECTABLE BY Q-PCR (EHA 2018) - "We confirm that IM+HCQ is a tolerable combination in CP-CML, with significant improvement in overall qPCR levels and MMR at 24 mth. This suggests that there may be a potential long-term benefit of combined therapy on qPCR levels and achievement of deep molecular response. Longer follow-up will be required to confirm this."

Clinical • P2 data • Residual disease • Chronic Myeloid Leukemia

Confirmatory study validates a MALDI prognostic signature for IL-2 response and the adverse prognostic role of the serum apoptotic marker Hepatocyte Growth Factor (HGF) in Renal Cell Carcinoma (RCC) (SITC 2018) - P1/2; "Trial Registration NCT01550367; approved as IRB 11-074.; Background Aldesleukin (recombinant interleukin-2, IL-2) was FDA-approved for mRCC in 1992 with a 5-10% rate of durable CRs and 25% ORR. Hydroxychloroquine (HCQ) inhibits autophagy, promoting tumor apoptosis...The prognostic power of the apoptotic marker and cMET ligand, HGF was confirmed. A combination of both markers showed potential for improved stratification, requiring future validation."

Biomarker • Melanoma • Renal Cell Carcinoma

Modulation of autophagy with hydroxychloroquine in patients with advanced non-small cell lung cancer (NSCLC): A phase Ib study. (ASCO 2018) - P1/2,P2; " Patients with newly diagnosed metastatic NSCLC were treated with carboplatin, paclitaxel (and bevacizumab if meeting criteria) and HCQ 200 to 600 mg BID for the escalation part and 600 mg BID for the expansion. Addition of HCQ has a similar toxicity profile compared to chemotherapy alone. The response rate to therapy in Kras mutated and wild type tumors was similar; even though Kras mutated tumors usually demonstrate worse responses and PFS to chemotherapy. Autophagy inhibition may help overcome chemotherapy resistance in patients with non-squamous NSCLC especially if Kras mutated."

Clinical • P1 data • Non Small Cell Lung Cancer

A pilot, phase I clinical trial to determine the biological effects of hydroxychloroquine (HCQ) on par-4 levels in patients with surgically removable solid tumors. (ASCO 2018) - P1; "To our knowledge, this is the first clinical trial indicative of HCQ as a robust inducer of Par-4 in cancer patients. The elevated levels of secreted Par-4 trigger paracrine apoptosis of cancer cells. The regimen of HCQ 200 mg twice daily was chosen for an ongoing adjuvant study."

Clinical • P1 data • Solid Tumor

Safety and activity of hydroxychloroquine and aldesleukin in metastatic renal cell carcinoma: A cytokine working group phase II study. (ASCO 2018) - P1/2; "NCT01550367 Background: Aldesleukin (recombinant human interleukin-2, IL-2) has been an FDA-approved treatment for mRCC since 1992 with a 5-10% rate of durable complete response. IL-2 plus HCQ was well tolerated and clinically active with encouraging PFS of 17 months at the 600 mg HCQ dose."

Clinical • P2 data • Renal Cell Carcinoma

Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG)in patients with advanced solid tumors. (ASCO 2019) - P1; "The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537"

Clinical • Combination therapy • P1 data

Modulation of autophagy: A Phase II study of vorinostat (VOR) plus hydroxychloroquine (HCQ) vs regorafenib (RGF) in chemo-refractory metastatic colorectal cancer (mCRC). (ASCO 2019) - P2; "VOR/HCQ did not improve survival when compared to RGF. VOR/HCQ has a favorable safety profile, but further planned subgroup analysis is pending to identify biomarkers of efficacy in responders. Clinical trial information: NCT02316340"

P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Full adaptome repertoire analysis of immunotherapy to predict responsiveness and correlation with CD8-LAG3, sLAG3, and hepatocyte growth factor levels in patients with renal cancer. (ASCO 2019) - P1/2; "Background: Aldesleukin (recombinant interleukin-2, IL-2), the first checkpoint inhibitor overcoming Tregs, was FDA-approved for mRCC with a 5-10% rate of durable CRs and 25% ORR. Hydroxychloroquine (HCQ) inhibits autophagy, promoting tumor apoptosis... IL-2 plus HCQ was well tolerated and clinically active with encouraging increase in the PFS of > 17 months at the 600 mg HCQ dose ( > 4x greater than historical controls). Powerful new technology identifying enhanced responsiveness correlating significantly with diversity of the TCR αβ identifies a novel method for predicting responsiveness to immunotherapy. This unbiased examination of the full repertoire ('Adaptome') measured in the same bioassay correlates with other novel biomarkers and should be widely applicable in the further evolution of immunotherapy."

Clinical • IO biomarker • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Health Economics of Steroid Refractory Chronic Graft-Versus-Host-Disease Treatments: Cost-Utility Based Meta-Analysis (BMT 2017) - "... Systematic search of literature for prospective and retrospective studies published from January 2000 to May 2016, examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis (ECP) and pomalidomide as a treatment for SR-cGVHD was done... This CEA illustrates significant variability in costs associated with various treatment modalities for cGVHD, accompanied by heterogeneous efficacy results. The lack of clinical trials directly comparing these agents and heterogeneity of trial designs and populations limit firm conclusions about incremental cost-effectiveness. Nevertheless, attention to economic issues when treating cGVHD is necessary to understand how treatments should be sequenced, knowing that many patients will cycle through available agents."

HEOR • Retrospective data • Biosimilar • Graft versus Host Disease

Efficacy of Caplacizumab in Patients with aTTP in the HERCULES Study According to Initial Immunosuppression Regimen (ASH 2019) - "Three patients (2.1%) received another type of initial immunosuppression (cyclophosphamide + corticosteroids [n=1], hydroxychloroquine [n=1], and mycophenolate mofetil + corticosteroids [n=1]), 1 patient (0.7%) started immunosuppression later in the study (cyclophosphamide + corticosteroids), while 5 patients (3.4%) did not receive any immunosuppressive treatment during the study...Immunosuppressive therapy intensification occurred in 38 patients (33.9%) initiated on corticosteroids alone (most often addition of rituximab [n=37], others included splenectomy [n=2], bortezomib [n=1], mycophenolate mofetil [n=1]), and in 3 patients (12.5%) initiated on corticosteroids with rituximab (bortezomib [n=1] and mycophenolate mofetil [n=3])... Immunosuppressive therapy in aTTP aims to control the underlying autoimmune disease, but requires time to take effect; this exposes patients to thrombotic complications and death. Caplacizumab treatment prevents disease exacerbations and..."

Clinical • Cardiovascular • Hematological Disorders • Immunology • Thrombocytopenic Purpura • Thrombosis

Longtime hydroxychloroquine users fear shortage as coronavirus increases demand (Daily News) - "Although the Food and Drug Administration has issued emergency authorization for the use of hydroxychloroquine for some hospitalized COVID-19 patients, Dr. Russell Buhr...is wary of the medication's effectiveness. A small French study that was at least part of the basis for Trump's endorsement of the drug raises 'red flags', Buhr said. 'As someone who does research, it makes me uneasy anchoring hope on one treatment that doesn't have much science to support it yet,' he added."

Media quote • Novel Coronavirus Disease

Combined inhibition of MEK and autophagy promotes regression of pancreatic cancer (AACR 2018) - "Most strikingly, whereas single agent therapy had modest effects, combined treatment of xenografted patient-derived PDAC tumors with trametinib plus chloroquine/hydroxychloroquine elicited striking tumor regression. Finally, the observed anti-tumor effects of combination trametinib plus chloroquine were observed against a NRAS mutated melanoma and a BRAF mutated colorectal patient-derived xenografts. These data may warrant testing this combination therapy in patients with KRAS mutated pancreatic cancers, a disease for which new pathway-targeted therapies are urgently required."

Melanoma • Pancreatic Cancer

Five important takeaways from recent COVID-19 recommendations (Healio) - "IDSA guideline panelist Rajesh T. Gandhi, MD, said the evidence supporting other therapies like hydroxychloroquine alone or in combination with azithromycin; lopinavir/ritonavir; tocilizumab; and convalescent plasma is uncertain. These agents should be evaluated in clinical trials to 'find out what works and what does not,' he noted....'The worst of the pandemic may have passed before COVID-19 related clinical trial results are published and, even then, there is no guarantee that the clinical trials will be definitive. Sometimes you must act based upon indirect evidence and clinical observations until the trial results become available,' he said."

Media quote

Gold nanoparticles-functionalized monolithic column for enantioseparation of eight basic chiral drugs by capillary electrochromatography. (PubMed, Mikrochim Acta) - "The pepsin@AuNP@poly(GMA-co-EDMA) monolith showed preferable enantioselectivity for hydroxychloroquine (HCQ), chloroquine (CHQ), hydroxyzine (HXY), labetalol (LAB), nefopam (NEF), clenbuterol (CLE), amlodipine (AML) and chlorpheniramine (CHL) in capillary electrochromatography (CEC). The reproducibility of intra-day, inter-day and column-to-column were explored, and found to be satisfactory. Graphical abstractSchematic presentation of the preparation of gold nanoparticles (AuNP) modified."

Journal • Acute Myelogenous Leukemia

Apremilast: a Potential Treatment for Dermatomyositis. (AAD 2018) - "...She was initiated on systemic steroids and continued to be steroid dependent despite trials of multiple immunosuppressive agents including: hydroxychloroquine, mycophenolate mofetil, azathioprine, methotrexate, soriatane, intravenous immunoglobulin, tacrolimus, chlorambucil, infliximab and rituximab...While on stable doses of mycophenolate mofetil and prednisone for 3 months, the patient was started on apremilast 30 mg twice a day...Apremilast, while not cytotoxic, can cause significant gastrointestinal effects. Apremilast can be added to other immunomodulating agents and offers an additional treatment option for those patients with recalcitrant dermatomyositis."

Biosimilar • Dermatology • Diabetes • Immunology • Inflammation • Myositis • Psoriasis

Strategies toward rheumatoid arthritis therapy; the old and the new. (PubMed, J Cell Physiol) - "DMARDs that are used for RA therapy are hydroxychloroquine, methotrexate, leflunomide, and sulfasalazine. The biological therapies, on the contrary, are chimeric anti-CD20 monoclonal antibody, rituximab, inhibitors of tumor necrosis factor-α (TNF-α) like etanercept, infliximab, and adalimumab, a recombinant inhibitor of interleukin-1 (IL-1), anakinra, and costimulation blocker, abatacept...The probability of remission increase if the diagnosis happens rapidly and treat-to-target approach are implemented. In this review article, we have attempted to go through the treatment strategies for RA therapy both the routine ones and those which have been developed over the past few years and currently under investigation."

Journal • Review • Immune Modulation • Immunology • Inflammation • Pain • Rheumatoid Arthritis

Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells. (PubMed, Cell Death Dis) - "In addition, combination treatment with Pae and an autophagy inhibitor (3-methyladenine and hydroxychloroquine) showed significant synergetic effects on inhibiting cell viability and promoting apoptosis in vitro and in the A2780 xenograft model, without severe side effects, which was often had by cisplatin...Furthermore, when combined with the inhibitors MK2206 and rapamycin to inhibit Akt and mTOR kinase activity, Pae-induced autophagy was increased. Taken together, our results demonstrate that Pae induced cytoprotective autophagy by inhibiting the Akt/mTOR pathway in ovarian cancer cells. Thus, the strategy of combining Pae with an autophagy inhibitor to block Akt/mTOR-dependent autophagy could enhance the antitumour activity of Pae and warrants further application for the treatment of ovarian cancer."

Journal • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor