Neoplasms

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Adenocarcinoma

Pancreatic Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Antirheumatic Agents

Gemcitabine

Paclitaxel

Hydroxychloroquine

Albumin-Bound Paclitaxel

Antimetabolites

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Abraxane: 125mg/m2 IV infusion over 30 minutes on Days 1, 8, 15 Gemcitabine: 1000mg/m2 IV infusion over 30-100 minutes on Days 1, 8, 15 Hydroxychloroquine: 1200 mg/day PO daily (600mg BID) Daily from D1

Abraxane: 125mg/m2 IV infusion over 30 minutes on Days 1, 8, 15 Gemcitabine: 1000mg/m2 IV infusion over 30-100 minutes on Days 1, 8, 15

Hydroxychloroquine (HCQ)

Abraxane

Peter O'Dwyer, MD

In this Phase I/II clinical trial, the investigators seek to pilot the addition of Hydroxychloroquine (HCQ) to a commonly-used front-line therapy of pancreatic cancer, gemcitabine/nab-paclitaxel. The investigators plan a run-in to define tolerable doses, and will explore doses of 800 and 1200 mg/day in successive cohorts of 6 patients. The investigators will assess toxicity continuously, and determine the dose for the Phase II trial based on standard toxicity criteria.

The correlative endpoints of this trial are directed to the pharmacokinetics of HCQ, and pharmacokinetic model of HCQ based on data from several ongoing trials, and the data from these patients will contribute to refining the model. The investigators will analyze both measured and model-predicted indices for their relationship to autophagy induction. Autophagy will be assessed as the accumulation of autophagocytic vesicles in the PMNs of treated patients, together with the induction of the expression of autophagy-related proteins on western analysis, quantitated by densitometry. The investigators will document the rates of metabolic response as a consequence of treatment, as a therapeutic marker that may be related to the degree of autophagy inhibition. Since the investigators have previously demonstrated a key role of JNK1 in the induction of autophagy by chemotherapy, the investigators will analyze archival tumor materials to determine variability in this marker, as a baseline for potential future trials. Finally, this study will incorporate metabolic profiling by mass spectrometry, which will be related to mutations (including Kras) in pretreatment tumor specimens. Mutational analysis will be accomplished by targeted sequencing or by next-generation sequencing, and the need for fresh tissue for all these endpoints will require patients to have a biopsy performed before treatment at at 6-8 weeks after beginning treatment. In the previous study of the Hh inhibitor GDC-0973 with the same chemotherapy, the investigators were able to obtain repeat biopsies successfully on all patients. The importance of these biopsies, to move the science forward in an era in which the tools now exist to provide meaningful correlative science, cannot be overstated.

Recent strategies have focused on improving the efficacy of gemcitabine either by improving the method of delivery, or by combining gemcitabine with other non-cross resistant agents. A sequence of Phase III combination studies of gemcitabine in combination (with oxaliplatin, and with the targeted therapies bevacizumab and cetuximab) have been negative, though based on strikingly positive Phase II data generated in cancer centers. Several studies suggest that taxanes are active in pancreatic cancer, but a randomized trial of gemcitabine with taxanes has not been preformed, probably on the basis that the differences in Phase II were insufficiently persuasive. The development of a novel taxane conjugate with albumin, abraxane, with established activity in breast cancer, prompted a Phase II trial of gemcitabine/abraxane by Von Hoff (6). Phase I/II data were highly promising, with response rates of the order of 40%, with tolerable toxicity, and a one-year survival of about 48%. A phase III trial of gemcitabine versus gemcitabine/abraxane is in progress, and based on these promising data has served as the control chemotherapy for previous SU2C trials. The development of a more intensive, but toxic regimen (FOLFIRINOX) in no way diminishes the enthusiasm for this chemotherapy backbone, given the activity in Phase II trials that appears comparable (7). Given the promise of this regimen, and the possibility of making a substantial improvement in outcome with additional targeted interventions, we propose to continue to use this regimen in the current study.

Of particular interest in extending these studies to pancreatic cancer is the finding that autophagy inhibition is particularly deleterious to cell lines bearing a mutant Kras protein. Additional studies as part of the SU2C pancreatic cancer project reveal that an autophagy program is activated in the presence of mutant Kras, and thus prompts the testing of this strategy in a setting in which Kras is commonly (about 85%) mutated (SU2C, unpublished data).

A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer

Abramson Cancer Center at Penn Medicine

Carcinoma, Hepatocellular

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Sorafenib

Protein Kinase Inhibitors

Sorafenib (SOR)-naïve patients receive SOR 400 mg by PO twice daily on Cycle1/Day1 (C1D1). In clinical practice, dose reduction of SOR is often required. Therefore, on C1D15, the clinician will dose-reduce sorafenib based on toxicity and hydroxychloroquine (HCQ) 400 mg PO daily will be started. C2D1 of each cohort, toxicity of HCQ will be assessed. Dose reductions due to adverse events (AEs) to each agent are allowed for SOR per standard of care and/or HCQ for grade 3+ AE.

As second-line treatment, we will add hydroxychloroquine (HCQ) to sorafenib (SOR) dose the patient was tolerating at the time of progression.

Patients will receive SOR 400 mg by PO twice daily on Cycle1/Day1 (C1D1).

Sorafenib (SOR)

Epp Goodwin

Sukeshi Patel Arora, MD

The PI is studying if sorafenib/hydroxychloroquine (HCQ) will have improved efficacy when compared to sorafenib alone and in patients progressing of sorafenib the addition of HCQ would lead to disease stability in patients with advanced hepatocellular cancer (HCC).

Phase 2 study with two cohorts:

Cohort 1: As second-line treatment, we will add HCQ to SOR dose the patient was tolerating at the time of progression.

Cohort 2: SOR-naïve patients receive SOR 400 mg by PO twice daily on Cycle1 Day1 (C1D1). On Cycle 1 Day 15, HCQ 400 mg PO daily will be started. In clinical practice, dose reduction of SOR may be required. On C1D15 SOR maybe kept as starting dose or reduced for toxicity. On Cycle 2 Day 1 of toxicity of HCQ and SOR will be assessed.

Each cycle is 28 days.

Blood samples will be collected at Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 to assess for biomarkers.

Disease evaluation every 2 cycles.

Dose reductions due to adverse events are allowed for both sorafenib per standard of care and/or HCQ for grade 3 or more adverse event was related to study medication. Dose reductions are also permitted based on investigator clinical decision.

Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer

Modulation of Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer

Computerized axial tomography (CAT) Scan or Magnetic resonance imaging (MRI) will be done at Screening, then every other cycle and evaluated using RECIST version 1.1

The University of Texas Health Science Center at San Antonio

Principal Investigator

Symptoms and General Pathology

Skin and Connective Tissue Diseases

Recurrence

Breast Neoplasms

Breast Diseases

Skin Diseases

Gastrointestinal Agents

Lipid Regulating Agents

Sucralfate

Antacids

Gedatolisib

Cholestyramine Resin

Anti-Ulcer Agents

Patients will receive HCQ, 600 mg BID, for 24 weeks.

Patients will receive HCQ, 600 mg BID, for 24 weeks and GED x 2 weeks administered weekly, as an intravenous dose of 150 mg.

Patients will receive HCQ, 600 mg BID, for 24 weeks and GED x 6 weeks administered weekly, as an intravenous dose of 150 mg.

Patients will receive HCQ, 600 mg BID, for 24 weeks and GED x 12 weeks administered weekly, as an intravenous dose of 150 mg.

Patients will receive HCQ, 600 mg BID, and GED, administered weekly as an intravenous dose of 150 mg, for 6 weeks.

All patients will receive HCQ at a dose of 600 mg orally twice daily. This dose is the same in both phase Ib and phase II portions of the protocol. Capsules of HCQ are available in 200 mg strength, thus patients will initially start with 3 capsules twice daily for a total of 6 capsules per day. HCQ will be administered in divided doses (BID). When taking HCQ twice daily, the two daily doses should be taken 12 hours apart as close to 9am and 9pm as possible. Patients receiving antacids, sucralfate, cholestyramine, and/or bicarbonate should have the HCQ drug dose administered at least 1 hour before or 2 hours after these medications. Hydroxychloroquine will be obtained from the UPENN Investigational Drug Service (IDS).

Gedatolisib will be administered intravenously on a weekly dosing schedule at 150 mg IV.

Within 3 days prior to GED dosing the patient must have an ANC \>1.0 x 109/L and platelet count \> 75 x 109/L. If hematologic toxicity persists, treatment should be delayed by one week and the complete blood cell count with differential and platelet count repeated. Treatment may be delayed for up to 4 consecutive weeks (28 days). If after 28 days of delay all hematologic toxicity has still not resolved to normal and non-hematologic toxicity has not resolved to \<grade 1 then any further treatment with GED should be stopped.

Angela DeMichele, MD

This clinical trial will assess the safety and early efficacy of the role of gedatolisib and hydroxychloroquine in early-stage breast cancer patients with residual disease and evidence of disseminated tumor cells (DTCs) on bone marrow aspirate after neoadjuvant chemotherapy (NACT) and definitive surgery.

24 participants in Phase Ib and 80 participants in Phase II

Gedatolisib, Hydroxychloroquine or the Combination for Prevention of Recurrent Breast Cancer ("GLACIER")

A Phase Ib/II Trial of Gedatolisib, Hydroxychloroquine or the Combination for Prevention of Recurrent Breast Cancer ("GLACIER")

Frequency of 'a priori' defined "severe" adverse events and any adverse event by NCI CTCAE v5 criteria (Phase Ib)

"Response" to treatment is defined by a greater than or equal to 50% reduction in number of disseminated tumor cells (DTCs) at 24 weeks compared to baseline (Phase II)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I/II/Pharmacodynamic Study of Hydroxychloroquine in Combination With Gemcitabine/Abraxane to Inhibit Autophagy in Pancreatic Cancer	NCT01506973	Advanced Adenoc... Metastatic Aden...	Hydroxychloroqu... Gemcitabine Abraxane	18 Years -	Abramson Cancer Center at Penn Medicine
Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer	NCT03037437	Hepatocellular ...	Sorafenib (SOR) Hydroxychloroqu...	18 Years - 100 Years	The University of Texas Health Science Center at San Antonio
Sorafenib Induced Autophagy Using Hydroxychloroquine in Hepatocellular Cancer	NCT03037437	Hepatocellular ...	Sorafenib (SOR) Hydroxychloroqu...	18 Years - 100 Years	The University of Texas Health Science Center at San Antonio
Gedatolisib, Hydroxychloroquine or the Combination for Prevention of Recurrent Breast Cancer ("GLACIER")	NCT03400254	Breast Cancer	Hydroxychloroqu... Gedatolisib	18 Years -	Abramson Cancer Center at Penn Medicine

Spots Global Cancer Trial Database for hydroxychloroquine (hcq)