Trial Of Melphalan Research Articles

A Phase II Trial of Melphalan Based Reduced Intensity Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients with Hematologic Malignancies

HLA-haploidentical (haplo) stem cell transplantation is now widely used for patients lacking a suitably matched related or unrelated donor (MUD). Conventionally, T-replete Haplo transplantation has been performed using non-myeloablative conditioning and a bone marrow graft. Subsequently, our group has developed the use of myeloablative conditioning and PBSC grafts for Haplo (Solomon et al BBMT 2015, 2019). However, some patients with hematologic malignancies who are unable to tolerate a fully myeloablative regimen may benefit from intermediate intensity conditioning. We conducted a prospective phase II trial utilizing melphalan based preparative regimen ( fludarabine 30mg/m2 days -6 to -2, melphalan 140 mg/m2 day -1) followed by infusion of unmanipulated peripheral blood stem cells (PBSCs) ,capped at 5x10 6 CD34+/kg,from a haploidentical first degree family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of Cy 50mg/kg on days 3 and 4, MMF through day 35, and tacrolimus through day 180. The primary endpoint was to estimate the incidence of graft rejection following Fludarabine/Melphalan conditioning. For the graft failure endpoint we tested the hypotheses H0: p=10% versus Ha: p<10% using a one-sided exact Binomial test. Assume that none of patients undergoing the proposed regimen will have graft failure, the power for confirming p less than 15% is always 100% if the null hypothesis is rejected. The population enrolled was needed to achieve rejection of the null hypothesis at the 5% significance level. Twenty-five patients had their first allogeneic transplant on this study, and their characteristics were as follows: median age 57 years (range 35-68), male sex 44%, transplant diagnosis included AML [11], ALL [3], MDS/MPN [7], NHL [3], and multiple myeloma [1]. Using disease risk index (DRI), patients were classified as low [1], intermediate [13], or high/very high [11]. Twenty patients (80%) had a comorbidity index (HCT-CI) of ≥ 3. Median follow up for survivors was 28.3 (range 8.7-43.9) months. Post infusion fevers that subsided after receiving Cytoxan were seen in 93% and two patients had grade 2 cytokine release syndrome. Median time to ANC and platelet engraftment was 18 days (13-32) and 36 days (21-224), respectively. Three patients failed to engraft with spontaneous count recovery in one of them. Two of the three graft failures ended up engrafting after a second transplant. All engrafting patients had sustained complete donor myeloid and T cell chimerism by day 30. Acute GVHD grade II-IV and III-IV was seen in 20% and 8% respectively. The cumulative incidence of chronic GVHD was 16% (moderate-severe 12%). The estimated 2-year overall survival (OS) was 56%, disease-free survival (DFS) 44%, non-relapse mortality (NRM) 20%, relapse rate 36% and GVHD-, relapse-free survival (GRFS) 41%. For patients with high/very high DRI, the 2 year OS was 53%. For patients with HCT-CI 0-2, 2 year OS and DFS were at 75%. When compared to a contemporaneous cohort of patients receiving haplo transplant using fludarabine, Cytoxan and low dose TBI (Baltimore regimen), outcomes were not significantly different for OS, DFS, NRM and relapse. Patients receiving Flu/Mel had lower incidence of acute II-IV GVHD at 100 days (16% vs 44%). A matched pairs comparison (n=18) using matching at age range, DRI and HCT-CI between Flu/Mel and patients receiving Flu/Cy/TBI at our center, showed significant difference in OS, DFS, NRM and relapse (graph 1) between Flu/Mel and flu/Cy/TBI. All patients with primary MPD (n=4) had successful engraftment on this protocol which historically had a high graft failure rate on the non-ablative flu/Cy/TBI. Haplo transplant using fludarabine/melphalan with PBSCs is a valid option for some patients lacking a timely access to a matched donor. It is well tolerated and provides full and rapid donor myeloid and T-cell chimerism. Figure 1:Overall Survival and Disease Free Survival In Matched Cohorts of Flu/Mel versus Flu/Cy/TBI Figure 1 Disclosures No relevant conflicts of interest to declare.

A phase I/II trial of melphalan (MEL) combined with panobinostat (PAN) for patients with relapsed or refractory (R/R) multiple myeloma (MM).

e18558 Background: PAN, a potent histone deacetylase inhibitor, significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity of standard chemotherapy. Studies with our SCID-hu MM models show an increased inhibition of MM cell growth when PAN was combined with MEL compared to treatment with either drug alone. These preclinical studies provided the rationale for evaluating the combination of oral MEL with oral PAN for the treatment of MM patients with R/R disease. Methods: This was a Phase 1/2, open-label, dose‑escalation study to treat R/R MM patients initially using oral PAN every Monday, Wednesday and Fridayin combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28‑day cycle. Results: Thirty-seven patients were enrolled into the Phase 1 portion of this study. The median number of prior regimens received were 4 (range, 1-17) with 22 patients previously treated with MEL. Following amendments to dose and schedule because of toxicity including cytopenias and fatigue, PAN and MEL were both administered only on days 1, 3 and 5 of a 28-day cycle. The maximum tolerated dose for this combination was defined as PAN at 20 mg and MEL at 0.05 mg/kg both administered on only days 1, 3 and 5. Overall, 4 patients (11%) showed objective responses to this combination with 1 complete (3%) and 3 partial (8%) responses and only occurred among patients receiving PAN throughout the cycle. An additional 18 (49%) patients had stable disease while 15 (41%) progressed while on study. Eighteen patients experienced grade 3 or 4 adverse events (AEs) with 6 of these meeting the definition of a dose-limiting toxicity. These AEs included reversible thrombocytopenia (n=11), reversible neutropenia (n=10), reversible worsening anemia (n=3), and one case each of a forearm rash, fatigue/weakness, pneumonia, hypokalemia and hyponatremia. Three more patients who are not yet evaluable have been enrolled into the Phase 2 portion to complete the planned 40 patients on the trial. Conclusions: The combination of intermittent PAN & low-dose oral MEL shows modest activity in heavily pretreated patients with R/R MM. Continuous doses of PAN with MEL yielded better efficacy but this treatment schedule was not tolerable.

A Randomized Phase I Trial of Melphalan + Bortezomib as Conditioning for Autologous Transplant for Myeloma: The Effect of Sequence of Administration.

Background: High dose therapy and autologous transplant (HDT) clearly benefits many patients with myeloma, but the addition of other chemotherapeutics or TBI to high dose melphalan (HDM) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor that synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data has shown that B upregulates the anti-apoptotic protein MCL-1, which would suggest that the sequence of administration may be critical to the combination of B and HDM. We hypothesize that B followed by M is inferior to M followed by B. To test this hypothesis, we designed a randomized phase I trial combining escalating doses of B and Melphalan 200 mg/ m2 (Mel200) in order to determine the toxicity, optimal dose and sequence of administration.Methods: Patients were randomized to receive either B 24 hours before Mel 200 (ARM A) or B 24 hours after Mel 200 (ARM B). Doses for B escalated from 1.0mg/m2 up to 1.6mg/m2 as defined using the Escalation with Overdose Control (EWOC) method, a Bayesian phase I design. Patients eligible for the study were required to have achieved no better than a PR following induction therapy, and to have measurable disease in the bone marrow. Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for annexin V staining, and myeloma cells were sorted for protein analysis. We compared the increase in annexin V and PI staining from the D-4 sample to D0 sample for each patient in order to determine which sequence was optimal for administration of B. Routine demographics, toxicity, and engraftment data were also collected.Results: 41 patients have been enrolled to date, with 34 evaluable for response assessment at day +100. B doses range from 1.0–1.6mg/m2 at both time points. Median age is 59 (44– 74). Median duration of ANC<500 and plts <20 was 11 and 5 days respectively, and was not different between the 2 bortezomib sequences. 20 patients have been randomized to ARM A of which 18 are evaluable for response, and 20 to ARM B of which 16 are evaluable for response. 18 of 34 (53%) evaluable patients achieved a VGPR or better at 100 days post transplant, with 32/34 (94%) achieving PR or better. The increase in annexin V and PI staining for the samples obtained from patients who were treated with the Arm B schedule of bortezomib was superior to the increase obtained with Arm A (see figure, p=ns). To date there is no difference in bone marrow IL6 or VEGF levels between the arms. There was no difference in mucositis or other toxicity between the 2 treatment arms.Conclusion: The combination of B and MEL 200 is a safe with engraftment kinetics and toxicity similar to that seen in a historical cohort receiving MEL 200 alone. Efficacy data is favorable when compared to the Mayo clinic retrospective analysis (Kumar BMT 2008) for a group of patients with similar tumor burden at the time of transplant (VGPR 55% current study vs 30% historical). Preliminary lab data suggests that the administration of B following MEL 200 may be superior to B before MEL 200. Data on DNA repair and additional cytokine secretion in the marrow will be presented. [Display omitted]

A Randomized Phase I Trial of Melphalan + Bortezomib as Conditioning for Autologous Transplant for Myeloma: The Effect of Sequence of Administration.

Background: High dose therapy and autologous transplant (HDT) benefits many patients with myeloma, but the addition of other chemotherapeutics or TBI to high dose melphalan (HDM) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor that synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data have shown that B up-regulates the anti-apoptotic protein MCL-1, which would suggest that the sequence of administration may be critical to the combination of B and HDM. We hypothesize that B followed by M will be inferior to M followed by B. To test this hypothesis, we designed a randomized phase I trial combining escalating doses of B and Melphalan 200 mg/m2 (Mel200) in order to determine the toxicity, optimal dose and optimal sequence of administration.Methods: Patients were randomized to receive either B 24 hours before Mel 200 (ARM A) or B 24 hours after Mel 200 (ARM B). Doses of B escalated from 1.0mg/m2 up to 1.6mg/m2 as defined using the Escalation with Overdose Control (EWOC) method, a Bayesian phase I design. Standard transplant criteria were used for enrolling myeloma transplant patients with the additional criterion of measurable disease at the time of transplant (>5% plasma cells by biopsy or M-protein >1.0). Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for annexin V staining on the plasma cell population, and myeloma cells were sorted for subsequent protein analysis. Routine demographics, toxicity, and engraftment data were also collected.Results: Twenty one patients have been enrolled to date, with 15 evaluable for response assessment. B doses range from 1.0–1.6mg/m2 with the current dose at 1.6mg/m2. Age range was 48–74 years. One patient had resistant disease at the time of transplant. Median time to WBC and Plt engraftment were 13 days and 15 days, and not different based upon B dose, sequence of administration, or historical patients treated with M alone. 10 patients have been randomized to the B.→ M arm, and 11 to the M.→B arm. 11 of 15 (73%) evaluable patients achieved a VGPR or better at 6 months post transplant, with an overall response rate of 14/15 achieving PR or better (93%). There were no significant differences in myeloma cell annexin V staining on day -4 between the 2 groups, however on the day 0 bone marrow, there was an increase in the percent of Annexin V (+) MM cells for the group randomized to the M.→B arm compared to the B.→M arm (45.3% vs 30%, respectively). To date there is no difference in bone marrow IL6 or VEGF levels between the 2 randomized groups though only 10 patients have been enrolled at the highest dose level.Conclusion: The combination of B and MEL 200 is safe with a toxicity profile and engraftment kinetics similar to that seen in a historical cohort receiving MEL 200 alone. Toxicity has been no different from our previous experience with MEL 200 alone. Preliminary lab data suggests that the M.→B arm may be superior to the B.→M arm. Data on DNA repair and additional cytokines will be presented.

150: A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma: The effect of sequence of administration

150: A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma: The effect of sequence of administration

A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma

17550 High dose chemotherapy and autologous transplant (HDT) clearly benefits most patients with myeloma, but the addition of chemotherapy or TBI to melphalan (M) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor which synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data has shown that B upregulates the anti-apoptotic protein MCL-1, which would suggest that B followed by M is inferior to M followed by B. We designed a randomized phase I trial combining B and Melphalan 200 mg/m2 (Mel200) in order to determine the toxicity, optimal dose and sequence of administration. Patients were randomized to receive either B 24 hours before Mel 200 or B 24 hours after Mel 200. Standard transplant criteria were used with the addition of requiring measurable numbers of plasma cells at the time of transplant. Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for apoptosis, and myeloma cells were sorted for protein analysis. Age range was 48–74 years. Prior therapy has included Velcade (n = 2, both responsive) thalidomide (n = 2) and prior melphalan in 2 (1 HDT). Time to WBC and Plt engraftment were not different from historical cohorts receiving MEL 200 alone. Four patients have been randomized to date with 3 in the B “before“ arm, and 1 in the B “after” arm. Of the 3 patients who received B before M, day 0 bone marrow revealed minimal changes in marrow myeloma cell apoptosis in two patients, and in one patient a &gt;20 fold increase in myeloma cell apoptosis on the day 0 marrow sample when compared to the day - 4 marrow. In the patient enrolled in the B after M arm, there was a 10 fold increase in the day 0 marrow myeloma cell apoptosis. Western blot analysis for DNA repair enzymes and MCL-1 on sorted tumor cells are planned, as is ELISA for secreted cytokines before and after therapy. Toxicity and response data with an update of the molecular correlates will be presented. The combination of B and M as conditioning for HDT is feasible. The optimal dose and sequence of administration remains unknown. Accrual continues. [Table: see text]

Phase II Trial of Methyl-gagand Melphalan in Metastatic Adult Renal Cell Carcinoma

A trial of melphalan and methyl-gag was undertaken in 16 patients with metastatic renal cell carcinoma. Among 14 evaluable patients, 6 had stabilization of disease. No significant responses were observed. While both drugs have produced occasional responses in renal cancer, their combination shows no therapeutic advantage.

A randomized trial of Melphalan alone versus combination chemotherapy in advanced ovarian cancer

A randomized trial of Melphalan alone versus combination chemotherapy in advanced ovarian cancer