Summary
Background:
DFP-10917 is a deoxycytidine nucleoside analogue with a unique mechanism of action resulting in leukemic cell death when administered for prolonged periods at low doses. This Phase I/II study was designed to determine the safety, tolerability, maximum tolerated dose (MTD) and evidence of anti-leukemic activity for DFP-10917 administered by 7- or 14-day continuous intravenous infusion (CI) in patients with relapsed or refractory acute myeloid leukemia (AML).
Methods:
In the Phase I dose escalation portion, patients with relapsed-refractory AML were administered DFP-10917 by 7-day CI followed by an approximate 21-day rest period (Stage 1), or 14-day CI followed by a 14-day rest period (Stage 2). Dose escalation used a standard 3+3 design guided by observance of first cycle dose-limiting toxicity (DLT). The primary objectives of the Phase I portion were to determine the (MTD, the dose recommended for Phase II study and the DLT of DFP-10917. The primary objective of the Phase II study were to evaluate the overall response rate of DFP-10917, as assessed by complete response (CR), CR without recovery of platelet (CRp) or lineage counts (CRi) or partial response.
Findings:
Eight dose levels of DFP-10917 (4 to 35 mg/m2/day) administered by 7-day CI were investigated for Phase I Stage 1. Due to the DLT of Grade 3 diarrhea at 35 mg/m2/day, the Phase I Stage 2 starting dose was established as 10 mg/m2/day over 14-days. In Phase I Stage 2, the dose of 10 mg/m2/day resulted in DLTs of prolonged hypocellularity and abdominal pain, diarrhea and vomiting. The 6 mg/m2/day dose administered over 14 days was well tolerated and was selected for Phase II. Among the 29 efficacy evaluable Phase II patients treated with DFP-10917 at 6 mg/m2/day by 14-day CI, 20.7% had CR, 3.4% had CRp, 24.1% had CRi. The overall marrow CR rate was 48.3% (95% CI: 29.4%, 67.5%).
Interpretation:
DFP-10917 given by 14-day CI at 6 mg/m2/day can be safely administered and is effective in relapsed-refractory AML. A phase III investigation comparing DFP-10917 monotherapy versus standard of care in an early relapse-refractory AML setting is warranted.
Funding:
Delta-Fly Pharma, Inc.
INTRODUCTION
Acute myeloid leukemia (AML) is a hematologic malignancy traditionally treated with cytotoxic chemotherapy. Initial induction therapy with cytarabine and an anthracycline has been the standard induction treatment of AML for several decades. As AML is characterized by numerous genetic abnormalities, there are a growing number of targeted agents in development intended to inhibit specific activating mutations. While many of these targeted agents are promising, cytotoxic chemotherapy remains a key component of AML therapy [1, 2].
DFP-10917 is a novel deoxycytidine analog, Its structure is 2’-C-cyano-2’-deoxy-1-β-D-arabino-pentofuranosyl-cytosine (CDNA; Figure 1) with a side-chain CN group that induces DNA damage in a manner unique from structurally related nucleoside analogs (e.g., cytarabine, decitabine, gemcitabine) [3]. When administered at a high dose, DFP-10917 is activated in the tumor cell through tri-phosphorylation at its 5’-OH. It then inactivates DNA polymerase, blocking DNA synthesis and leading to S-phase arrest, similar to the mechanism of action known for cytarabine and gemcitabine. When DFP-10917 is administered as a continuous low dose infusion, the tri-phosphorylated DFP-10917 incorporates into replicating DNA and self-generates single-strand breaks (SSBs) through β-elimination (Figure 1). These SSBs are further metabolized to double-strand breaks (DSBs) during a subsequent, delayed S-phase when the replication fork encounters the SSB, followed by an arrest in G2/M phase. This leads to cell apoptosis unless the DSB is repaired through the homologous recombination pathway. Studies in human tumor xenograft in mice showed prolonged continuous infusion rather than short-term administration of DFP-10917 was more effective in slowing the growth of tumor cells in vivo.
Figure 1.
Mechanism of DFP-10917 DNA Strand Break
Two Phase I studies in solid tumors and one Phase II study in patients with colorectal cancer were previously conducted with DFP-10917. The Phase I studies evaluated both 14-day continuous infusion of DFP-10917 followed by a 7-day rest period and 7-day continuous infusion of DFP-10917 followed by a 7-day rest period schedules. The maximum tolerated dose (MTD) of each 14-day and 7-day treatment was 2.0 mg/m2/day and 3.0 mg/m2/day, respectively. The dose-limiting toxicity (DLT) was myelosuppression. The Phase II study was a Simon-two stage design in 26 patients with chemotherapy-refractory advanced colorectal cancer, evaluating a 14-day continuous infusion of DFP-10917 followed by a 7-day rest period. The Phase II study did not proceed past the first stage because it did not meet the tumor response rate required to enter into Stage 2. Myelosuppression was evident in each of the trials and supported the concept that bone marrow cells have a higher sensitivity to DFP-10917 that could be explored as a potential new therapy for acute leukemia.
PATIENTS AND METHODS
Study Design
This was s single institution Phase I/II open label study conducted in the Leukemia Department at MD Anderson Cancer Center. The Phase I dose-escalation portion consisted of 2 stages and was designed to determine the highest tolerable dose and regimen (7- or 14-day continuous infusion) of DFP-10917 based on safety data in patients with refractory or relapsed AML. Patients were enrolled in ascending dose cohorts of 3+3 patients and were monitored for evidence of first cycle DLTs and DFP-10917 plasma concentration. In Stage 1, patients were administered a starting dose of 4 mg/m2/day 7-day continuous infusion followed by a 21-day rest period. The starting dose for the 14-day infusion (Stage 2) was determined by the MTD and adverse event profile observed among the 7-day infusion (Stage 1) cohort. The primary objectives of the Phase I dose-escalation portion were to determine the MTD, the dose recommended for Phase II study (RP2D) and the DLT of DFP-10917 in patients with refractory or relapsed AML. The secondary objectives were to assess the overall response rate (CR, CRp, CRi or PR) to DFP-10917 treatment and the PK profile of the drug.
The Phase II portion investigated the safety and efficacy of DFP-10917 at the dose and regimen determined in the Phase I portion, in patients with refractory or relapsed AML. The primary objective was to evaluate the overall response rate (ORR) of DFP-10917. The secondary objectives were to evaluate complete remission rate (CR) and CR without recovery of platelet counts (CRp) or of lineages counts (CRi) duration of complete remission, duration of overall response and overall survival in after DFP-10917 treatment.
The Phase II design was based on a Simon two-stage optimal design [4]. All patients who completed at least one treatment course of DFP-10917 and had at least one post-treatment clinical response assessment were considered eligible for the efficacy evaluation. Dose reductions were allowed if clinically indicated (e.g., adverse event meeting the DLT criteria). Patients were permitted to continue on-study in the absence of progressive disease, as long as toxicity remained acceptable. Response and progressive disease was assessed based on the International Working Group (IWG) response criteria [5].
Tolerability and Safety Assessments
Adverse events were graded in accordance with the National Cancer Institute Common Terminology Criteria (CTCAE), version 4.0. Physical examination, vital signs, solicitation of AEs, hematology and clinical chemistry were performed at baseline and throughout the study.
Patients who completed treatment without progressive disease, withdrawal of consent, or death remained on-study and were followed for response every 6 weeks until progressive disease was documented or until a new anti-leukemia therapy was initiated (whichever occurred first). Survival was assessed every 2 months following disease progression for up to 12 months.
The protocol was approved by the institutional Review Board., All patients signed an informed consent according to the Declaration of Helsinki (NCT01702155).
Patients
In the Phase I portion, patients aged ≥18 years with pathologically documented acute leukemia meeting at least one of the following criteria were enrolled: refractory or relapsed after standard therapy for the disease or an ineffective conventional systemic chemotherapy. Eastern Cooperative Oncology Group performance status of <3 and absence of cardiac, renal and CNS illnesses were required.
In the Phase II portion, eligibility was limited to histologically confirmed diagnosis of AML (based on WHO classification), being refractory after standard therapy, or for which conventional systemic chemotherapy was not reliably effective, or no effective therapy was available. Patients aged 60 years or older with newly diagnosed AML who were not eligible for, or who refused standard care were also considered eligible.
Exclusion criteria for both the Phase I and II portions included an interval of < 2 weeks from prior treatment to time of study drug administration for cytotoxic agents or < 5 half-lives for non-cytotoxic agents. Patients could not have had any > Grade 1 persistent, clinically significant toxicities from prior radiotherapy. Patients with acute promyelocytic leukemia (APL) or with known Hepatitis B (HBV) or C (HCV) or HIV infection were also excluded from the study.
There was no restriction on the number of prior treatment regimens. Concomitant use of hydroxyurea was permitted for up to 5 days during the first 28 days of the study.
Pharmacokinetics
Serial plasma samples were collected from patients during the first cycle of the Phase I portion of the study and analyzed for levels of DFP-10917 (CNDAC) and its primary metabolite, CNDAU, using a validated assay. PK plasma samples were analyzed by Drug Metabolism and Analysis Department of LSI Medience Corporation (Ibaraki, Japan).
Response to Treatment
In the Phase II portion of the study, efficacy, as measured by ORR was the primary endpoint. Secondary efficacy was determined by the overall complete remission rate, duration of overall complete remission, duration of overall response, and overall survival. Patients underwent bone marrow aspirates and/or biopsies at screening and prior to the start of each new treatment cycle. Response and progressive disease was assessed based on the IWG response criteria [5]
Statistical Analyses
In the Phase I portion of the study, demographic and summary statistics was used to describe the study population, while efficacy and safety (laboratory parameters, vital signs and AE) data was tabulated for all patients.
The Phase II portion of the study was based on a Simon two-stage optimal design [4]. It was assumed that a response rate equal to 5% (P0 = 0.05) or less would be undesirably low, whereas a response rate of at least 20% (P1 = 0.20) would justify further study of DFP-10917. All patients registered on-study were considered eligible for the intent-to-treat (ITT) population and summarized for demographics, and efficacy. All patients who completed at least one treatment cycle of DFP-10917 were considered eligible for the efficacy-evaluable population. At the time of the efficacy analysis, patients alive with no disease progression or lost to follow-up had their duration of response censored at the date of the last clinical response. Patients who received a new therapy had their duration of response censored at the date of their last clinical response. Patients alive had their survival time censored at the date of last time known alive. For the durations of overall response, overall complete remission and survival, life table estimate were calculated using Kaplan-Meier methodology [6]. The 95% confidence intervals was calculated for the median survival time based on the Brookmeyer-Crowley methodology [7]. All patients who received any DFP-10917 were considered eligible for the safety population, and safety data (adverse events, vital signs, and laboratory parameters) was tabulated.
RESULTS
Patient Characteristics
A total of 69 patients were enrolled in the study, 39 in the Phase I portion (27 in Stage 1, 12 in Stage 2) and 30 in the Phase II portion. The patient characteristics are summarized in Table 1. All patients had a diagnosis of AML. All patients were previously treated. The percentage of patients with ≥ 3 prior treatment regimens was 53% for the Phase I portion and 33% for the Phase II portion (Table 1).
Table 1.
Patient Characteristics Phase I/II Study of DFP-10917
| Characteristic | Phase I (N = 39) | Phase II (N = 30) | Total (N = 69) |
|---|---|---|---|
|
| |||
|
| |||
| Gender | |||
| Female; n (%) | 14 (36) | 12 (40) | 26 (38) |
| Age, years | |||
| Median (range) | 69 (26–85) | 71(45–88) | 70 (26–88) |
| ≥ 65 | 26 (66.7) | 22 (73) | 48 (70) |
| AML; n (%) | 39 100 | 30 100 | 69 100 |
| Duration of disease; median (range in months) | |||
| Median | 9.23 (1–116) | 6.6 (0–136) | 8.7 (0–136) |
| Number of prior chemotherapy regimens; n (%) | (N = 38) | (N = 30) | (N = 68) |
| 1 | 9 (24) | 8 (27) | 17 (25) |
| 2 | 9 (24) | 12 (40) | 21 (31) |
| 3 | 5 (13) | 5 (17) | 10 (15) |
| 4 | 6 (16) | 1 (3) | 7 (10) |
| ≥ 5 | 9 (24) | 4 (13) | 13 (19) |
Karyotype Diploid ≥ 3 abnormalities
Safety and Tolerability
In the Phase I Stage 1, eight dose levels of DFP-10917 (4 to 35 mg/m2/day) administered by 7-day continuous infusion were investigated. At the 35 mg/m2/day dose level, one patient experienced a Course 1 DLT of Grade 3 diarrhea, and 2 additional patients completed Cycle 1 study treatment without DLTs. Due to an adverse event of Grade 3 tremor that occurred in one patient during Course 2 of treatment at the 25 mg/m2/day dose level and evidence of transient anti-leukemic effect among several patients treated in the Stage 1, the investigator and sponsor decided to calculate the Phase I Stage 2 starting dose based on a 7-day infusion dose of 30 mg/m2/day. By calculating the cumulative dose of DFP-10917 administered over 7-days and dividing by 14, a conservative Phase II starting dose of 10 mg/m2/day 14-day continuous infusion was selected.
In Phase I Stage 2, at the dose level of 10 mg/m2/day administered by 14-day continuous infusion, 2 of 4 patients who completed Course 1 treatment experienced DLTs: one had prolonged hypocellularity and delayed bone marrow recovery and the second experienced Grade 3 abdominal pain, diarrhea and vomiting. These two patients were subsequently treated at the reduced dose of 6 mg/m2/day and one patient had a further dose reduction to 4 mg/m2/day due to delayed bone marrow recovery and received a total of 21 cycles; the other patient continued DFP-10917 at 6 mg/m2/day and received a total of 5 cycles. Therefore, the next cohort of patients was treated at the reduced dose of 6 mg/m2/day. Among the 7 patients in Phase I treated with a 14-day infusion of DFP-10917 at 6 mg/m2/day no Grade 3 or 4 non-hematologic adverse events occurred during the first treatment course, except for one incidence of Grade 3 fatigue. Therefore, the dose of 6 mg/m2/day administered by 14-day continuous infusion was confirmed as the MTD/RP2D.
In Phase II, no suspected unexpected serious adverse events (AEs) or deaths related to DFP-10917 occurred. Grade 3 or greater drug-related AEs were decreased white blood cell count (16 patients, 53.3%), decreased platelet count (14, 46.7%), anemia (11, 36.7%), decreased neutrophil count (5, 16.7%) and fatigue (1, 3.3%). Among the 7 patients who received 3 to 6 courses of DFP-10917, four patients required a dose reduction to 4 mg/m2/day due to prolonged myelosuppression resulting in delayed initiation of subsequent treatment course and due to fatigue (one patient) (Appendix Table).
Pharmacokinetic Profile
DFP-10917 concentrations at Day 8 (steady-state) for 4 – 35 mg/m2/day dose and 7-day continuous infusion were 1.49 to 28.9 ng/mL. The slope of plasma concentration versus dose was 0.6402 with removal of two cases of outlier values. CNDAU (metabolite) concentrations at Day 8 were 3.49 to 40.1 ng/mL. The slope of plasma concentration versus dose was 1.0660 (Appendix; Figure 1).
DFP-10917 concentrations for 6.0 or 10 mg/m2/day dose and 14-day continuous infusion were 4.21 to 7.58 ng/mL on Day 8 and 4.81 to 5.92 ng/mL on Day 15 or 2.05 to 12.4 ng/mL on Day 8 and 3.67 to 10.8 ng/mL on Day 15, respectively. CNDAC concentrations at 6.0 or 10 mg/m2/day dose were 8.21 to 15.3 ng/mL on Day 8 and 6.63 to 13.0 ng/mL on Day 15 or 6.98 to 19.4 ng/mL on Day 8 and 7.51 to 16.6 ng/mL on day 15, respectively. The DLT events were associated with the higher CNDAC systemic concentrations.
Response to Treatment
Phase I: For Stage 1 (7-day continuous infusion followed by 21-day rest), 1 of 23 efficacy evaluable patients had a CRi, occurring at the 6 mg/m2/day dose level. The ORR was 4.3% (95% CI: 0.1%, 21.9%). For Stage 2 (14-day continuous infusion followed by 14-day rest), among the 10 efficacy evaluable patients treated at 10 mg/m2/day or 6 mg/m2/day, 2 patients treated at 10 mg/m2/day achieved a CR and 7 of these 10 patients demonstrated a ≥50% decrease in bone marrow blasts. One patient (82 years) treated initially at 10 mg/m2/day with subsequent dose reductions to 6 mg/m2/day and 4 mg/m2/day due to prolonged delayed marrow recovery received 21 cycles of treatment with continuous remission. Due to the superior ORR, the 14-day continuous infusion followed by 14-day rest schedule was selected for the RP2D.
Phase II: Among the 29 evaluable patients treated at the DFP-10917 6 mg/m2/day dose by 14-day continuous infusion, 6 (20.7%) had CR, 1 (3.4%) had CRp, 7 (24.1%) had CRi and 2 (6.9%) had SD for 8 weeks; the ORR and the Overall Complete Response/ Remission Rate were both 48.3% (95% CI: 29.4%, 67.5%) (Table 3).
Table 3.
Best Overall Response Phase I/II Study of DFP-10917
| Best Overall Response[1][2] | Phase I (N = 33) | Phase II (N = 29) | Total (N = 62) | |||
|---|---|---|---|---|---|---|
|
| ||||||
| No. | % | No. | % | No. | % | |
|
| ||||||
| Complete Remission (CR) | 2 | 6 | 6 | 21 | 8 | 13 |
| Complete Remission/incomplete platelet (CRp) | 0 | 1 | 3 | 1 | 2 | |
| Marrow CR/incomplete blood count (CRi) | 1 | 3 | 7 | 24 | 8 | 13 |
| Stable Disease for 8 weeks (SD) | NA | 2 | 7 | 2 | 3 | |
| Treatment Failure (TF) | 30 | 91 | 13 | 45 | 43 | 69 |
| Overall Response (CR+CRp+CRi+PR) | 3 | 9 | 14 | 48 | 17 | 27 |
| Lower 95% Confidence Limit | 2 | 29 | 17 | |||
| Upper 95% Confidence Limit | 24 | 68 | 40 | |||
| Overall Complete Response/Remission (CR+CRp+CRi) | NA | 14 | 48 | NA | ||
| Lower 95% Confidence Limit | NA | 29 | NA | |||
| Upper 95% Confidence Limit | NA | 68 | NA | |||
Overall Response based on patients with either a CR, CRp, CRi, or PR. Overall Complete Response/ Remission based on patients with either a CR, CRp, or CRi.
Clopper-Pearson method used for the calculation of the 95% confidence interval.
NA=Not Applicable
Of the 14 responders to DFP-10917 treatment in the Phase II, the median duration of response was 137 days (95% CI: 75 days, 208 days; Figure 2). The progression-free rate was 92.9% at 1 month (30 days), 64.3% at 3 months (90 days), 50.0% at 4 months (120 days) and 42.9% at 6 months (180 days).
Figure 2.
Duration of Response and Survival in the Phase II Efficacy Evaluable Patients (N=29)
Survival
In Phase II, the median overall survival time was 221 days (95% CI: 118 days, 284 days; (Figure 2). The overall survival rate was 58.6% at 6 months (180 days)) and 20.7% at 1 year (360 days).
Five of the 30 patients treated in Phase II underwent stem cell transplantation (SCT) after achieving CR or CRi. Each of these 5 patients had previously undergone induction therapy with an anthracycline and cytarabine, and DFP-10917 was the patient’s 3rd or 4th treatment regimen.
DISCUSSION
Cytarabine remains a mainstay of AML induction therapy in combination with an anthracycline. At low doses and with prolonged exposure, DFP-10917 functions by inducing single-strand breaks in leukemic cell DNA that converts to double-strand breaks resulting in cell death. This contrasts with the activity of cytarabine by DNA polymerase interference and DNA strand incorporation.
The Phase I/II study of DFP-10917 in relapsed-refractory AML demonstrated that the 14-day continuous administration of DFP-10917 at a dose of 6 mg/m2 with 14-day rest is well-tolerated and exhibits a substantial level of anti-leukemic activity as a single agent. Eleven of the 14 Phase II patients that demonstrated a response to DFP-10917 had prior combination chemotherapy that included cytarabine. Seven of the Phase II responding patients completed 3 to 6 cycles of DFP-10917, and only 2 required a dose reduction to 4 mg/m2/day due to prolonged hypocellularity. Five of the Phase II responders, who had prior anthracycline and cytarabine induction treatment, were transitioned to stem cell transplant after achieving remission with DFP-10917 monotherapy. The results indicated that DFP-10917 may improve the outcome of advanced AML patients, but also demonstrated that DFP-10917 anti-leukemic effect can be induced at a higher dose (6 mg/m2/day) and be maintained at a lower less toxic dose (4 mg/m2/day).
The overall response rate of 48% among the 29 efficacy evaluable patients is substantial for a single agent approach in relapsed-refractory AML. The overall response rates in a Phase II trial of elacytarabine, an elaidic acid ester of cytrarabine, demonstrated an overall remission rate of 18% among 61 relapsed-refractory AML patients who had received at least 2 induction regimens. The Phase III overall response rate for elacytarabine among relapsed-refractory AML patients was 23% (8, 9). In a Phase II trial of sapacitabine, an oral formulation of the CNDAC molecule used in DFP-10917, patients 70 years or older with untreated or first relapsed AML who received oral sapacitabine achieved an overall response rate of 15% to 18% depending on the sapacitabine dose and schedule. (10)
The demonstrated therapeutic efficacy of DFP-10917 monotherapy administered by continuous infusion for 14-days of 28 day cycles is a promising treatment for multiply relapsed AML. Further evaluation of DFP-10917 in a randomized Phase III study in AML is planned.
Figure 3. Duration of Response and Survival.
Duration of Response and Survival in the Phase II Efficacy Evaluable Patients (N=29)
Table 2.
Incidence of Common (≥ 10%) and All Grade 3– 4 Related Adverse Events
| Preferred Term and Grade | Phase I/ Stage 1 (N = 26) | Phase I/ Stage 2 (N = 12) | Phase II (N = 30) | Total (N = 68) | ||||
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| No. | % | No. | % | No. | % | No. | % | |
|
| ||||||||
| White blood cell count decreased | ||||||||
| Total | 15 | 58 | 7 | 58 | 16 | 53 | 38 | 56 |
| Grades 3–4 | 15 | 58 | 7 | 58 | 16 | 53 | 38 | 56 |
| Nausea | ||||||||
| Total | 11 | 42 | 6 | 50 | 7 | 23 | 24 | 35 |
| Grades 3–4 | 0 | 0 | 0 | 0 | ||||
| Diarrhea | ||||||||
| Total | 9 | 35 | 7 | 58 | 6 | 20 | 22 | 32 |
| Grades 3–4 | 1 | 4 | 1 | 8 | 0 | 2 | 3 | |
| Platelet count decreased | ||||||||
| Total | 3 | 12 | 3 | 25 | 14 | 47 | 20 | 29 |
| Grades 3–4 | 3 | 12 | 3 | 25 | 14 | 47 | 20 | 29 |
| Alopecia | ||||||||
| Total | 2 | 8 | 5 | 42 | 9 | 30 | 16 | 24 |
| Grades 3–4 | 0 | 0 | 0 | 0 | ||||
| Anemia | ||||||||
| Total | 1 | 4 | 2 | 17 | 11 | 37 | 14 | 21 |
| Grades 3–4 | 1 | 4 | 2 | 17 | 11 | 37 | 14 | 21 |
| Constipation | ||||||||
| Total | 2 | 8 | 3 | 25 | 7 | 23 | 12 | 18 |
| Grades 3–4 | 0 | 0 | 0 | 0 | ||||
| Decreased appetite | ||||||||
| Total | 2 | 8 | 3 | 25 | 2 | 7 | 7 | 10 |
| Grades 3–4 | 0 | 0 | 0 | 0 | ||||
| Vomiting | ||||||||
| Total | 3 | 12 | 3 | 25 | 1 | 3 | 7 | 10 |
| Grades 3–4 | 0 | 1 | 8 | 0 | 1 | 2 | ||
| Fatigue | ||||||||
| Total | 1 | 4 | 1 | 8 | 4 | 13 | 6 | 9 |
| Grades 3–4 | 0 | 0 | 1 | 3 | 1 | 2 | ||
| Neutrophil count decreased | ||||||||
| Total | 1 | 4 | 0 | 5 | 17 | 6 | 9 | |
| Grades 3–4 | 1 | 4 | 0 | 5 | 17 | 6 | 9 | |
| Lymphocyte count decreased | ||||||||
| Total | 4 | 15 | 1 | 8 | 0 | 5 | 7 | |
| Grades 3–4 | 4 | 15 | 1 | 8 | 0 | 5 | 7 | |
| Febrile neutropenia | ||||||||
| Total | 1 | 4 | 1 | 8 | 0 | 2 | 3 | |
| Grades 3–4 | 1 | 4 | 1 | 8 | 0 | 2 | 3 | |
| Abdominal pain | ||||||||
| Total | 0 | 1 | 8 | 0 | 1 | 2 | ||
| Grades 3–4 | 0 | 1 | 8 | 0 | 1 | 2 | ||
| Hypocalcaemia | ||||||||
| Total | 1 | 4 | 1 | 8 | 0 | 2 | 3 | |
| Grades 3–4 | 1 | 4 | 0 | 0 | 1 | 2 | ||
| Tremor | ||||||||
| Total | 1 | 4 | 0 | 0 | 1 | 2 | ||
| Grades 3–4 | 1 | 4 | 0 | 0 | 1 | 2 | ||
Note: Severity was defined by National Cancer Institute Common Terminology Criteria for Adverse Events version 4. There were no Grade 5 treatment-related adverse events.
Appendix
Figure 1.
DFP-10917 and metabolites pharmacokinetic (Pk) profile in patients [Need much better figure here] Move to end-Appendix.
Footnotes
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
KI, CJ and CZ are employees of Delta Fly Pharma, Inc. Grant research support by Delta Fly Pharma, Inc. for the study. No other Conflict of Interests exists among the authors.
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