Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid

We administered liposome-encapsulated all-trans retinoic acid (L-ATRA) to 48 patients with refractory hematologic malignancies using an every- other-day schedule for 28 days and doses of 15 to 175 mg/m2. In 19 patients, pharmacology studies were conducted after the first (day 1) and seventh (day 15) doses. In contrast to the decline in tretinoin concentration seen within 3 to 4 days of administration of daily oral ATRA, there were no differences between the area under the curve (AUC) of tretinoin concentration versus time on day 1 and day 15 (P = .98, Wilcoxon signed-rank test). Peak day 1 concentrations after 15 mg/m2 were higher than those reported after 45 mg/m2 oral ATRA. Six patients with relapsed acute promyelocytic leukemia (APL) were treated. Three, each in first relapse and at least year from the last exposure to oral ATRA, achieved a complete response (CR). Disease recurred in two (one at 3 months despite maintenance L-ATRA and similarity in tretinoin AUC on days 1 and 85, and the other at 5 months, 2 months after discontinuation of L-ATRA) and the third was transplanted 1 month into CR. The three nonresponders were in at least a second relapse and failed to respond to oral ATRA before or immediately after receiving L- ATRA. Severe toxicity developed in three of eight patients treated at 175 mg/m2 (joint pains in two, skin in one). The maximum tolerated dose (MTD) was determined to be 140 mg/m2, at which dose grade 2 toxicity (primarily headache and skin) occurred in eight of eight patients, but grade 3 to 4 toxicity in none. Compared with oral ATRA, L-ATRA apparently results in greater exposure to tretinoin and for a longer time.

Download Full-text

All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.8.1489 ◽

1993 ◽

Vol 11 (8) ◽

pp. 1489-1495 ◽

Cited By ~ 40

Author(s):

R Kurzrock ◽

E Estey ◽

M Talpaz

Keyword(s):

Retinoic Acid ◽

Side Effects ◽

Myelodysplastic Syndrome ◽

Acid Tolerance ◽

Maximum Tolerated Dose ◽

Significant Activity ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Biologic Effects ◽

Dose Levels

PURPOSE We conducted a study to evaluate the tolerance to and biologic effects of all-trans retinoic acid in patients with myelodysplastic syndrome. PATIENTS AND METHODS Thirty-nine patients with myelodysplastic syndrome were treated with oral all-trans retinoic acid for 6 weeks. Dose levels were 10, 25, 50, 100, 150, 200, and 250 mg/m2/d. At least three patients were treated on each dose level. RESULTS The most common side effects were mucocutaneous dryness and erythema, and hypertriglyceridemia. Dose-limiting side effects were diverse and included dermatitic problems, sensorineural hearing loss, headaches, nausea and vomiting, myalgias, and dyspnea. The maximum-tolerated dose was 150 mg/m2/d. Only one response was seen among 29 patients considered assessable for response. CONCLUSION All-trans retinoic acid can be safely administered to patients at doses up to 150 mg/m2/d for 6 weeks. However, as administered in this study, this compound does not appear to have significant activity in myelodysplastic syndromes.

Download Full-text

All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results [see comments]

Blood ◽

10.1182/blood.v76.9.1704.1704 ◽

1990 ◽

Vol 76 (9) ◽

pp. 1704-1709 ◽

Cited By ~ 821

Author(s):

S Castaigne ◽

C Chomienne ◽

MT Daniel ◽

P Ballerini ◽

R Berger ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Complete Response ◽

Clinical Results ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Hepatic Transaminases

Abstract Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases-- were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.

Download Full-text

Phase I evaluation of all-trans-retinoic acid in adults with solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.5.959 ◽

1993 ◽

Vol 11 (5) ◽

pp. 959-966 ◽

Cited By ~ 51

Author(s):

J S Lee ◽

R A Newman ◽

S M Lippman ◽

M H Huber ◽

T Minor ◽

...

Keyword(s):

Retinoic Acid ◽

Phase I ◽

Solid Tumors ◽

Phase Ii ◽

Squamous Cell ◽

Peak Plasma ◽

Maximum Tolerated Dose ◽

Skin Reactions ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

PURPOSE Prompted by recent demonstrations that all-trans-retinoic acid (all-trans-RA) had efficacy in acute promyelocytic leukemia, a phase I trial of all-trans-RA was conducted to establish the maximum-tolerated dose (MTD) before phase II testing. PATIENTS AND METHODS Forty patients with a histologic or cytologic diagnosis of malignancy other than leukemia were treated with single daily oral doses of all-trans-RA ranging from 45 mg/m2 to 200 mg/m2. Doses of all-trans-RA were escalated in the next cohort of patients until the MTD was determined if the preceding dose level was not associated with significant toxicity. RESULTS Lung cancer was the most common type of tumor included in the study (26 cases) followed by head and neck squamous cell carcinomas (three cases), and squamous cell carcinoma of the skin (two cases); other miscellaneous solid tumors were also represented. Toxicities included cheilitis, skin reactions, headache, and nausea and vomiting, as well as transient elevations of liver enzymes and triglyceride levels. Skin toxicities, consisting of erythema with desquamation and paronychia, were considered to be the dose-limiting toxicity, and were observed in two of six patients who received 175 mg/m2/d, and in two of five patients who received 200 mg/m2/d. Of the 30 patients with assessable lesions, response was evaluated in 26 patients and no major objective tumor response was observed. Two patients were able to receive the drug for longer than 1 year without significant toxicities. There was considerable variation in individual patients' peak plasma all-trans-RA levels, and a decrease in the area under the curve of all-trans-RA plasma concentration was observed in all four patients evaluated. CONCLUSION For phase II study of adult patients, we recommend 150 mg/m2 of all-trans-RA administered orally once a day. However, for better optimization of drug administration schedules, further studies are needed.

Download Full-text

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer

Nature Communications ◽

10.1038/s41467-020-18636-w ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Hemant M. Kocher ◽

Bristi Basu ◽

Fieke E. M. Froeling ◽

Debashis Sarker ◽

Sarah Slater ◽

...

Keyword(s):

Clinical Trial ◽

Retinoic Acid ◽

Controlled Trial ◽

Locally Advanced ◽

Maximum Tolerated Dose ◽

Assessment Method ◽

Pancreatic Stellate Cells ◽

Ductal Adenocarcinoma ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid

Abstract Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1–15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6–15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.

Download Full-text

All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results [see comments]

Blood ◽

10.1182/blood.v76.9.1704.bloodjournal7691704 ◽

1990 ◽

Vol 76 (9) ◽

pp. 1704-1709 ◽

Cited By ~ 19

Author(s):

S Castaigne ◽

C Chomienne ◽

MT Daniel ◽

P Ballerini ◽

R Berger ◽

...

Keyword(s):

Retinoic Acid ◽

Acute Promyelocytic Leukemia ◽

Complete Response ◽

Clinical Results ◽

Promyelocytic Leukemia ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Hepatic Transaminases

Twenty-two patients with acute promyelocytic leukemia were treated with all-trans retinoic acid (RA, 45 mg/m2 per day) for 90 days. Of the 22, four patients were previously untreated, two were resistant after conventional chemotherapy, and 16 were in first (n = 11), second (n = 4), or third (n = 1) relapse. We observed 14 complete response, four transient responses, one failure, and three early deaths. Length of hospitalization and number of transfusions were notably reduced in complete responders. Correction of coagulation disorders and an increase of WBCs were the first signs of all-trans RA efficacy. Morphologic analysis performed at days 0, 15, 30, 45, 60, and 90 showed that complete remissions were obtained without bone marrow (BM) hypoplasia. Presence of Auer rods in the maturing cells confirmed the differentiation effect of the treatment. At remission, the t(15;17) initially present in 20 patients was not found. The in vitro studies showed a differentiation in the presence of all-trans RA in 16 of the 18 tested cases. The single nonresponder to all trans RA in vitro did not respond in vivo. Adverse effects of RA therapy--skin and mucosa dryness, hypertriglyceridemia, and increase of hepatic transaminases-- were frequently noted. We also observed bone pain in 11 patients and hyperleukocytosis in four patients. Whether maintenance treatment consisted of low-dose chemotherapy or all-trans RA, early relapses were observed. Five patients are still in complete remission (CR) at 4 to 13 months. Our study confirms the major efficacy of all-trans RA in M3, even in relapsing patients. Remissions are obtained by a differentiation process.

Download Full-text

Pattern of extramedullary relapse in latin patients with acute promyelocytic leukemia (APL) treated with all-trans-retinoic acid (ATRA) and chemotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.17520 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 17520-17520

Author(s):

L. A. Casanova ◽

S. M. Quintana ◽

S. P. Neciosup ◽

C. A. Samanez

Keyword(s):

Retinoic Acid ◽

High Risk ◽

Rare Event ◽

Disease Free Survival ◽

Complete Response ◽

Free Survival ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Extramedullary Relapse ◽

Disease Free

17520 Background: Extramedullary relapse (EMR) is a rare event in APL and reports have suggested a possible rol of ATRA in its pathogenesis. Our study intent to determine the pattern of EMR in Latin patients treated whit trans-retinoic acid (ATRA) and chemotherapy (CT). Methods: We evaluated 87 patients diagnosed of APL from January 2001 to December 2005. They were treated with ATRA and chemotherapy. Results: 74/87 received ATRA plus chemotherapy. Median age was 28 (5–68). 39/74 (53%) patients were female. Subtype M3v constituted 21/74 (28%). 76% presented disseminated intravascular coagulation (DIC). Extramedullary deposit was observed in 7 cases, more frequent was central nervous system (CNS). According the Sanz Index, 32/74 (32%) were High Risk, 40/74 (54%) Intermediate Risk, 2 Low Risk. 31/55 (56%) presented t(15,17). 52/74 (70%) patients had complete response. EMR was documented in 8 (15%) (CNS: 5, External Auditory Foramen: 3), 4 were High Risk. Median time to EMR was 11.5 months (7.03–27.3). 55% are alive at date. The following median was 36 months, 41 months of Disease Free Survival (DFS), rate was 62 % to 3 years. Overall survival was 44 months; rate was 83% to 3 years. Conclusions: EMR incidence was 8%, higher report that other series, this event was presented in CNS and external auditory foramen. It suggest to establish EMR risk factors and to include CNS prophylactic treatment. No significant financial relationships to disclose.

Download Full-text