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ACTG Salvage Study: DAPD + MMF
  This is a study in the ACTG currently looking to recruit additional patients to complete enrollment. It appears that the use of investigational drugs is liberal and access to Fuzeon & tipranavir is available.
ACTG 5165 "DAPD vs. DAPD + MMF in Treatment Experienced Subjects"
A Multicenter Trial of the Adult AIDS Clinical Trials Group (AACTG)
Sponsored by:
The National Institute of Allergy and Infectious Diseases
30 of the 56 patients needed to complete the study have now been enrolled. Further enrollment of patients is needed in completing the study.
Antiviral therapy in the setting of advanced drug resistance is difficult to provide and to study, even with antiviral agents of new classes. ACTG 5165 is a potentially important study, as it both tests the activity of a new nucleoside RT inhibitor (DAPD) and the ability of mycophenolate (MMF) to safely enhance antiviral activity in patients with drug resistance and (usually) advanced disease.
While there are other studies within and without the ACTG for patients with advanced disease and drug resistance, ACTG 5165 does offer significant opportunities for the optimization of background therapy. The study provides a virtual phenotype to guide selection of background therapy and the study provides enfuvirtide (T-20) if selected by the patient. Further, expanded access medications such as Tipranavir are allowed as part of background therapy.
The provision of DAPD has been assured by Gilead until the end of the study, and the rights to develop the drug have been assumed by a new industry sponsor (to shortly be announced publicly). Interim safety reviews have revealed no toxicity concerns related to DAPD or MMF thus far.
Study Rationale
The antiretroviral activity of DAPD is variable in subjects with prior NRTI experience. The potency of DAPD can be markedly increased in vitro against NRTI-resistant HIV-1 variants by the addition of 0.25 μM MPA. Preliminary clinical data suggest that 500 mg BID of MMF is well tolerated in subjects with advanced HIV-1 disease. This dose of MMF achieves trough plasma levels of 0.81 to 5.20 µM, which after adjusting for protein binding, may exceed the in vitro concentration of MPA (0.25 μM) needed to enhance the activity of DAPD against NRTI-resistant HIV-1 variants. However, no clinical data currently exist on the activity of DAPD combined with MMF. This will be the first such study in treatment-experienced patients.
To minimize the duration of exposure of subjects in this trial to potentially suboptimal therapy, a 2-week primary endpoint with unblinding for non-responders has been selected. This endpoint is based on the dynamics of virologic response to antiretroviral therapy observed by Polis et al. (10).
I don't know which site this study is offered at, so you will have to check. But the study chair is David Margolis who is based in Dallas so for sure the study will be at his site. I also think its at NYU in addition to other ACTG sites including Pittsburgh, Harvard,
DESIGN: This is a phase I/II, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the safety, tolerability, and antiretroviral activity of β-D-2,6-diaminopurine dioxolane (DAPD) alone or in combination with mycophenolate mofetil (MMF). HIV-infected adults with HIV-1 RNA >= 2000 copies/mL on their current antiretroviral regimen will be enrolled.
SAMPLE SIZE: 56 subjects (28 per arm)
POPULATION: Antiretroviral-experienced HIV-infected men and women at least 18 years of age who have virologic failure (plasma HIV-1 RNA >= 2000 copies/mL) on their current antiretroviral regimen. Subjects should have been on their current regimen, which may not include abacavir, for at least 30 days prior to entry, and have a screening viral load >= 2000 copies/mL and a screening CD4+ cell count >=100 cells/mm3.
STRATIFICATION: Subjects will be stratified by screening plasma HIV-1 RNA level (< 40,000 or >= 40,000 copies/mL).
Step 1, Blinded Treatment
At entry subjects must agree to remain on their current antiretroviral regimen through week 2. Eligible subjects will be randomized to one of the following treatment arms to be added to their current regimen:
Arm A: DAPD 500 mg BID + MMF placebo BID (n=28)
Arm B: DAPD 500 mg BID + MMF 500 mg BID (n=28)
Beginning at week 2, subjects have the option of optimizing their background antiretroviral regimen based on the results of their pre-entry resistance assay.
Subjects who do not respond virologically will be unblinded and enter Step 2. Subjects who respond virologically will be encouraged to remain on blinded study treatment (Step 1) through week 24, when all subjects are unblinded and registered to Step 2.
Step 2, Unblinded Study Treatment or Off Treatment On Study
After unblinding, subjects may add MMF, if they were not already receiving it. Response to the addition of open-label MMF will be assessed after 2 weeks. Resistance to antiretroviral agents (including DAPD) will be assessed following virologic failure that occurs after week 2.
Step 3, Weeks 52-96
Subjects who are still receiving DAPD alone or DAPD + MMF at week 48 and who are still responding virologically may be registered to Step 3 and continue to receive the study drug(s) and be followed for up to an additional 48 weeks. There will be no Step 3 if there are no subjects still receiving any study drugs and responding virologically at week 48.
β-D-2,6-Diaminopurine Dioxolane (DAPD)
DAPD is a purine nucleoside analogue currently undergoing phase II evaluation. DAPD is metabolized to dioxolane guanosine (DXG), which has potent in vitro activity against wild-type and zidovudine-resistant HIV-1 variants including those containing the multi-NRTI resistance insert at codon 69. In vitro, DAPD/DXG selects for the K65R and L74V mutations in HIV-1 reverse transcriptase, which confer low-level (3-6 fold) phenotypic resistance to the drug (1).
In a 14-day, dose-escalation study, treatment-naïve patients received DAPD doses of 25, 100, 200, 300, 500 mg BID, or 600 mg QD, and treatment-experienced patients received DAPD doses of 200, 300, or 500 mg BID. The median baseline CD4+ count of patients in all dose groups ranged from 210 to 561 cells/mm3. The median baseline plasma HIV-1 RNA in all dose groups ranged from 3.96 log10 to 5.05 log10 copies/mL. Treatment-experienced patients were generally heavily pretreated having a median time on antiretroviral therapy of 4 years and having exposure to a median of seven antiretroviral drugs. In treatment-naïve patients, the median maximum reduction in HIV-1 RNA was 0.37, 0.79, 1.14, 1.3, 1.1, and 0.79 log10 copies/mL in the 25 mg BID, 100 mg BID, 200 mg BID, 300 mg BID, 500 mg BID, and 600 mg QD dose groups, respectively. In treatment-experienced patients, the median maximum reduction in HIV-1 RNA was 0.38, 0.23, and 0.64 log10 copies/mL in the 200 mg, 300 mg,and 500 mg BID dose groups. Comparison of HIV-1 genotypic profile from patients' plasma at baseline and day 14 showed no new mutations in RT. All doses of DAPD tested were well tolerated with no discontinuations due to toxicity. In summary, DAPD was well tolerated and showed antiretroviral activity in both naïve and treatment-experienced patients, although the reduction in HIV-1 RNA was consistently lower in experienced patients than in naïve patients, indicating that strategies to enhance the activity of DAPD in experienced patients are needed.
The emergence of HIV-1 resistant to DXG has been examined in vitro. Selection of HIV-1 with mutations associated with resistance to DXG occurs slowly and with prolonged exposure to increasing concentrations of drug during passage of HIV in tissue culture (up to 13 to 14 passages or up to 70 days of passage in cell culture [unpublished data, Triangle Pharmaceuticals, Inc.]). The studies revealed that drug resistance to DXG is the result of one of two mutations (K65R or L74V) within the reverse transcriptase gene. Virus containing the K65R mutation showed moderate cross-resistance to ddC, ddI, adefovir, tenofovir (TDF), and 3TC, while sensitivity to ZDV was moderately increased. Introduction of the K65R mutation into a ZDV resistant background reversed ZDV resistance. Virus encoding the L74V mutation was resistant to ddI, slightly cross-resistant to 3TC, and slightly more sensitive to ZDV than wild type. Clinical HIV-1 isolates obtained from subjects who had failed ZDV, 3TC, and/or NNRTI therapy remained sensitive to DXG. DXG has been shown to have synergistic in vitro anti-HIV activity when used in combination with a variety of other antiretroviral compounds. DXG remains active against virus with the 69 insertion mutations, but is 5-fold less active against virus with the Q151M mutation complex (2).
Toxicology studies of up to 12 months duration have been completed in mice, rats, marmoset monkeys, and cynomolgus monkeys. In all species, the major toxicity observed was obstructive nephropathy, believed to be caused by precipitation of DAPD or DXG in kidney tubules. Three cynomolgus monkeys with obstructive nephropathy also had hyperglycemia, early formation of eye lens opacities, and islet cell atrophy. Like acyclovir, DAPD and its active metabolite, DXG, have limited aqueous solubility and are eliminated primarily through the kidney. A dose of 100 mg/kg/day for 1 year produced no evidence of obstructive nephropathy or any other toxicity in cynomolgus monkeys. This no-effect dose produced plasma exposures in cynomolgus monkey that are anticipated to exceed human exposure to DAPD and DXG at a dose of 500 mg DAPD BID (by 440% and 150%, respectively). The observed obstructive nephropathy was reversible when detected early and dosing was stopped, and can also be readily monitored in clinical settings. Subjects with renal insufficiency may be at greater risk for obstructive nephropathy and should not be dosed with DAPD until additional clinical testing is completed.
To date two serious adverse events have been reported in clinical trials of DAPD. Neither of these events was considered by the investigators to be related to DAPD. One patient was hospitalized with intermittent chest tightness and discomfort and associated shortness of breath to rule out myocardial infarction. The patient was discharged from the hospital on the following day with noted improvement in symptoms. The patient completed the 14-day dosing part of the study. The chest discomfort (chest pain) resolved on study day 16. Another patient was hospitalized for pneumonia and presumptive Mycobacterium Avium complex (MAC) infection. The patient had completed 14 days of DAPD dosing and then on study day 22 was hospitalized for fatigue, productive cough, shortness of breath, headache, and fever. The patient initially responded to antibiotic treatment and was discharged. However, on study day 40, the patient was re-hospitalized, and a diagnosis of MAC was made.
Overall, all doses of DAPD tested have been well tolerated in 14-day studies with no discontinuations due to toxicity. The most frequently occurring side effects have been headache (20%), pain (15%), nausea (12%), diarrhea (12%), rash (12%), abdominal pain (11%), malaise (11%), and tooth disorder (11%). There was no apparent dose-response relationship for any of the adverse events (AEs) observed. Most of the AEs were mild and transient and were not considered by the investigator to be related to the study drug.
One patient in the 200 mg BID cohort who had a history of kidney stones had an episode of renal colic and passed a kidney stone on day 1 of the study. He had normal creatinine levels. The study medication was continued unchanged. He completed the study with no additional renal problems.
There were very few Grade 3 or 4 laboratory abnormalities observed. In the 100 mg BID cohort, one patient who discontinued after day 1 had a Grade 4 creatine kinase (CK) at his termination visit. In the 200 mg BID cohort, one patient had a one-grade shift in CK from Grade 3 at screening to Grade 4 post baseline. One patient in the 300 mg BID cohort had a Grade 3 triglyceride elevation. In the study of DAPD in treatment-experienced patients, one patient in the 300 mg BID cohort with a Grade 2 neutrophil count at screening, had a Grade 3 neutrophil count on day 15. In the 500 mg BID cohort, Grade 3 abnormalities were in CK or triglycerides, none of which was deemed to be related to DAPD. There were no dose-related trends in treatment-emergent laboratory abnormalities. There were no treatment-emergent grade shifts or Grade >= 2 abnormalities in serum creatinine levels. Thus far, there is no evidence of renal toxicity with DAPD over the 14 days of DAPD dosing.
On the basis of animal toxicology data, there is a potential concern that a DAPD overdose could cause obstructive nephropathy, hyperglycemia, and/or cataracts. Treatment for an overdose of DAPD should include hydration of the subject and monitoring of renal function tests. No specific information is available for other manifestations of overdose at this time. If an overdose occurs, appropriate medical management, including immediate gastric evacuation, should be considered. Appropriate medical supportive care should be continued until any suspected obstructive nephropathy is ruled out or any clinical or laboratory AE returns to baseline or to a medically acceptable level.
Mycophenolic acid
Mycophenolic acid (MPA) is a potent, selective, noncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), and thus inhibits the de novo synthesis of guanosine nucleotide synthesis (3). This effect is specific for lymphocytes because the predominant pathway for GTP synthesis in lymphocytes is the de novo pathway, whereas other cell types are able to efficiently utilize the salvage pathway for GTP synthesis. The addition of MPA has been shown to lower the in vitro anti-HIV EC50 values of guanosine(G)-analogue NRTI including ABC, DAPD, and DXG (4,5,6,7). MPA reduces the intracellular concentration of guanosine triphoshate (GTP), which increases the ratio of the G-analogue-TP to dGTP. This effect increases the likelihood that the chain terminating GTP-analogue will be incorporated by HIV-1 reverse transcriptase.
In vitro, MPA has been observed to antagonize the antiviral effect of AZT and D4T against NRTI-sensitive HIV (6). It is not known if this effect will be seen in vivo. Although reports are so far anecdotal, increases in HIV viral load have not been observed when ribavirin, another IMPDH inhibitor that demonstrates antagonism against AZT and D4T in vitro, has been administered to patients receiving zidovudine or stavudine.
The effects of MPA on the antiviral activity of DAPD, DXG, and other NRTIs are summarized in Table 1 (personal and confidential communication, Triangle Pharmaceuticals):
Addition of 0.25 μM MPA had the greatest effect on the antiviral activity of DAPD and DXG decreasing the apparent EC50 by 16.7-fold and 10.5-fold, respectively. This effect was larger with DAPD or DXG than with abacavir (ABC) or other nucleoside analogues.
The effect of MPA on the activity of DAPD and DXG against NRTI-resistant variants of HIV-1 was also analyzed. The resistant variants included viruses created by site-directed mutagenesis encoding K65R and L74V, as well as those encoding A98S, F116Y, Q151M, and T215Y. Addition of 0.25 μM MPA decreased the EC50 values of DAPD and DXG against the resistant viruses to those observed for wild type virus, as shown below, in Table 2:
Mycophenolate Mofetil
Mycophenoate mofetil (MMF), an ester of mycophenolic acid (MPA), is currently indicated for the prevention of organ rejection in allogeneic renal and cardiac transplantation and is usually administered in renal transplant patients at 1000-1500 mg twice a day in combination with cyclosporine and corticosteroids. After rapid oral absorption, MMF is hydrolyzed to form MPA, the active metabolite.
MMF is available as CellCept®. Several studies have been conducted to test the combination therapy of ABC with MMF in HIV-infected patients. In one study (4), eight HIV-infected patients who had received ABC plus amprenavir (APV) for at least 72 weeks also received MMF in addition for 24 additional weeks. These patients were compared with eight patients who only received ABC plus APV. MMF was dosed at 500 mg BID for the first 4 weeks and 1000 mg BID thereafter. Because patients had undetectable viral loads at baseline, the intent of this study was to investigate the safety of MMF and its effects on CD4+T cell counts. Although there was no decrease in the absolute values in the total CD4+ cells, MMF decreased the pool of activated CD4+ cells. The combination of MMF with ABC and APV was safe for over 24 weeks; no hematologic toxicity or profound immunosuppression was reported. No significant effects on CD4+ counts or on HIV-1 RNA levels were observed.
An open-label pilot study of APV, ritonavir (RTV), didanosine (ddI), ABC, and MMF (250 mg BID) showed that the combination was well tolerated in seven symptomatic patients with AIDS and multidrug-resistant HIV-1 following the failure of eight or more prior antiretrovirals (5). No significant decline in lymphocyte or other blood counts was observed. Mean CD4+ cell count was 30/µL at entry, 43/µL at 4 weeks of therapy, and 46/µL at 16 weeks of therapy. Mean HIV-1 RNA was 5.3 log10 copies/mL at entry, 3.6 log10 copies/mL at 4 weeks, and 4.8 log10 copies/mL at 16 weeks. Few new changes in HIV-1 RT or PR genotypes were noted at the HIV-1 RNA nadir or following HIV-1 RNA rebound. Of interest, fluorescence-activated cell sorter (FACS) analysis showed significant decreases (3-fold to 4-fold) in markers of T-cell activation (CD69+) and apoptosis (annexin V) to levels comparable with those in normal HIV-1-negative controls in four of five patients evaluated after 16 weeks of therapy. This finding is striking in light of the modest increases in CD4+ cell counts and the waning of the maximal antiretroviral effect between weeks 4 and 16. There was no evidence of significant toxicity related to the use of MMF in the study volunteers despite advanced immune deficiency. No evidence of further depletion of CD4+ or CD8+ cell counts was observed. However, one patient who had HIV-1 RNA decrease to <50 copies/mL and CD4+ cell count increase from 7 to 73/µL developed a cauda equina neurologic syndrome. No evidence of cytomegalovirus (CMV) infection was found. In this patient, no improvement has been observed after 3 months of therapy with foscarnet and ganciclovir.
In another pilot clinical trial (8), MMF 500 mg BID was added to the antiretroviral regimens of five patients in whom current antiretroviral therapy was failing. Therapy included ABC, and in most cases ddI and tenofovir disoproxil fumarate (TDF). At entry, mean plasma HIV-1 RNA was 5.02 log10 copies/mL (median 4.78, range 4.71-5.63) and mean CD4+ count was 106/mm3 (median 117, range 11-174). MMF was well-tolerated. CD4 cell counts did not decline significantly from baseline for up to 60 weeks of follow-up. Three of five patients had HIV-1 RNA declines of >0.5 log10 copies/mL immediately after adding MMF; a fourth patient had a persistent >0.5 log10 copies/mL at week 12. Declines of >0.5 log10 copies/mL were lost in two patients at 6 and 8 weeks, and persist in two patients at 36 and 60 weeks of follow-up, respectively. An increase in the ratio of carbovir triphosphate (CBV-TP), the active metabolite of ABC, to dGTP was documented in three of four patients in temporal association with decreases in HIV-1 RNA. Trough plasma MPA levels ranged from 0.26-1.67 µg/mL; peak levels 90 minutes after dosing ranged from 1.20-7.77 µg/mL. The AUC of MPA appeared little changed when measured over 28 weeks of therapy.
AE information has been accumulated in transplant patient populations (3). The frequency of AEs due to MMF is dose related and a function of the intensity and duration of immunosuppression. The most common side effects are diarrhea and vomiting. Diarrhea was reported in 16.4% of organ transplant subjects taking 2000 mg/day of MMF and in 13.9% of those receiving placebo. Leukopenia and anemia were also more commonly reported in organ transplant subjects taking 2000 mg/day of MMF (10.9% and 4.2%, respectively) than in those receiving placebo (4.2% and 1.8%, respectively). Although the sepsis syndrome and respiratory infection were reported more frequently in organ transplant subjects taking 2000 mg/day of MMF than in those receiving placebo, documented systemic infection or pneumonia was not more common in subjects receiving MMF. Invasive CMV infection was reported more frequently in organ transplant subjects taking 2000 mg/day of MMF than in those receiving placebo (3.0% vs. 2.4%); herpes simplex virus (HSV) and herpes zoster were also reported more frequently.
Finally, over 1 year on study, lymphoma/lymphoproliferative disease was reported in 0.6% of organ transplant subjects taking 2000 mg/day of MMF, 0.3% of those taking azathioprine, and 0% of those receiving placebo (3). Because of the risks of immunosuppression with MMF at doses of 2000 mg/day, the package insert warning states that "Only physicians experienced in immunosuppressive therapy . . . should use MMF. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information for the follow-up of the patient."
Overall, MMF has been well tolerated in pilot studies performed in HIV-infected individuals, as noted above (9). In addition, another 20-week trial assessed the tolerability and antiviral activity of MMF in combination with ABC plus other antiretroviral agents in heavily antiretroviral-experienced subjects who were failing their current treatment regimens. HIV-1 genotyping at entry showed three or more reverse transcriptase (RT) mutations conferring resistance to ABC and RT mutations conferring significant NNRTI resistance or three or more protease gene mutations predictive of a poor response to all available PIs. Five subjects with CD4+ cell counts ranging from 13 to 170 cells/mm3 (mean value of 66 cells/mm3) were enrolled. All subjects received ABC 300 mg PO BID and MMF 250 mg PO BID in addition to two or three other antiretroviral agents. There were no significant drug-related toxicities, declines in CD4+ or CD8+ cell counts, or exacerbations of cutaneous viral infection or mucocutaneous candidiasis during the course of the trial. One subject developed an episode of pyleonephritis associated with leukopenia. This volunteer had received intermittent therapy with granulocyte colony-stimulating factor (G-CSF) prior to study entry but did not receive G-CSF after enrollment.
Another 8-week dose-escalation trial of MMF plus ABC was conducted in six subjects to assess the effect of MMF on the in vivo susceptibility of ABC-resistant virus to ABC. MMF was administered in a dose-escalation fashion: 250 mg PO BID during week 1, 500 mg PO BID during week 2, 750 mg PO BID during week 3, and finally, 1000 mg PO BID during week 4 and through to the end of the trial at week 8. CD4+ cell counts in the six volunteers ranged from 10 to 258 cells/mm3 with a mean value of 91 cells/mm3. MMF appeared to be well tolerated. No evidence of leukopenia or further depletion of CD4+ or CD8+ cell counts was observed. One volunteer developed an episode of HSV esophagitis at week 6 with the 2000 mg/day dose. Study medication was discontinued, the subject was treated with acyclovir, and the clinical symptoms resolved. An additional volunteer who had pre-existing visual complaints was noted to have CMV retinitis on a follow-up eye examination at the 2000 mg/day dose. The subject was treated with a ganciclovir implant without complications. One volunteer complained of diarrhea 1 week after beginning the 2000 mg/day dose that resolved with dose reduction to 750 mg BID. MMF at daily doses of 500 mg to 1500 mg was well tolerated without evidence of significant toxicity. However, a causal relationship between high-dose MMF (2000 mg per day) with clinical immune
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