A Phase 1 Study of Oral MRX-1024 in Combination With Standard Fractionation Radiation Therapy and High-Dose Cisplatin in Patients With Squamous Cell Carcinoma of the Head and Neck Following Surgical Resection
Each patient progresses through five study phases.
MRX 1024 Cohorts, Dose Levels and Treatment
Five successive dose levels are planned.
MRX 1024 Combination Treatment Phase Cohort Combination Treatment Phase MRX 1024 Schedule
MRX 1024 Dose Level once daily in cohorts 1, 2, and 3 twice daily in cohorts 4 and 5)
Initial Cohort Size 1 One daily dose given 30 minutes before each dose of RT 50 mg kg 3
patients 2 One daily dose given 30 minutes before each dose of RT 75 mg kg 3 patients 3 One
daily dose given 30 minutes before each dose of RT 100 mg kg 3 patients 4a Two daily doses:
one given 30 minutes before and one given 30 minutes after each dose of RT 75 mg kg 3
patients 5a Two daily doses: one given 30 minutes before and one given 30 minutes after each
dose of RT 100 mg kg 3 patients
Because of the logistics of delivering radiation therapy, the two daily doses of MRX 1024
given to patients in cohorts 4 and 5 will be approximately 75 to 90 minutes apart.
To ensure accurate and compliant dosing, MRX-1024 treatment must be administered in the
Beginning on Day 1 of Week 1 of the Combination Phase, patients will begin receiving MRX
1024 in conjunction with radiation and cisplatin or carboplatin, chemotherapy.
MRX 1024 will be given prior to each day's radiation fraction, and again following each
day's radiation fraction for patients being treated in cohorts 4 and 5. If a scheduled
radiation treatment is not given, the MRX 1024 dose should not be given on that day.
Dose escalations will occur in successive cohorts as indicated in Table 5 above, based on
the rules for dose level escalation as described in Table 6, below. Intra-patient dose
escalation is not permitted. No dose adjustments of MRX 1024 are permitted. If a patient
experiences a DLT that precludes further treatment with MRX 1024, MRX 1024 treatment will be
discontinued. That patient will continue on study, receive radiation therapy and cisplatin
or carboplatin, according to the protocol, and be followed on study through the Follow Up
The next higher dose level will be opened for enrollment after:
1. the preceding dose level has enrolled three patients,
2. two of these patients have completed Days 1 through 42
3. the third patient has completed four weeks of the Combination treatment
4. none of these patients experiencing a dose limiting toxicity.
If one patient being treated in an open dose level experiences a DLT during this interval,
then 3 more patients must be enrolled and all six patients in that dose level must be
followed for a minimum of the 42 day interval described above before a decision can be made
regarding further enrollment and escalation to the next higher cohort. If no additional
patient experiences a DLT in that cohort, then the next higher cohort will be opened for
If greater than 2 patients in a cohort experience a DLT, then that cohort is considered to
have exceeded the maximum tolerable dose level. Three additional patients will then be
enrolled to the next lower cohort using that treatment schedule The objective of the dose
escalation scheme is to identify a safe, tolerable and potentially efficacious dose level
using the once daily dosing schedule and a potentially efficacious dose level using the
twice daily dosing schedule of MRX-1024 in which less than 1 of 6 patients experiences a
Dose Level Escalation Rules
Number of Patients in a cohort with DLTa at a Given Dose Level Escalation Dose Rule 0 out of
3. Enter 3 patients at the next higher dose level. If cohort 3 and or cohort 5 are
completed with 0 out of 3 patients experiencing a DLT, then enroll 3 additional patients to
each respective cohort. greater than 2 Dose escalation will be stopped. This dose will be
declared to have exceeded the maximum tolerable dose. Enroll 3 additional patients at the
next lower cohort using that MRX 1024 dosing schedule. If this occurs in cohort 1, 25 mg kg
will be used as the next lower dose level.
1 out of 3 Enter 3 more patients in this cohort at this dose level. If 0 of these 3
additional patients experience a DLT , then begin enrollment at the next higher cohort. If
1 or more of these 3 additional patients experience a DLT then dose escalation will be
stopped. This dose will be declared to have exceeded the maximum tolerable dose. Enroll 3
additional patients at the next lower cohort using that MRX 1024 dosing schedule. If this
occurs in cohort 1, use 25 mg kg as the next lower dose level. Less than 1 out of 6 at the
highest tolerable dose level
This is generally the Recommended Dose for subsequent clinical trials. a See Section 4.5 for
the definition of Dose-Limiting Toxicity
If a patient does not complete the Combination Treatment Phase for any reason related to
intolerance of MRX 1024, this will constitute a DLT and the patient will not be replaced in
the study. If a patient does not complete the Combination Treatment Phase for any reason
unrelated to MRX 1024 and the patient did not experience a DLT, an additional patient will
be enrolled in the study. Data from the original patient will remain as part of the study
database but that patient's adverse event experience will not be used to evaluate the safety
of MRX 1024 at that dose level.
After the study has ended, an additional analysis of the safety data will be performed to
evaluate potential alternate dosing schemes. The doses used in the five dose levels
described above will be converted on an individual patient basis to approximate fixed doses
and also to mg body surface area dosing. Based on the additional analyses, a preferred
dosing scheme will be recommended for subsequent clinical trials.
Radiation therapy begins on Day 1 of Week 1 of the Combination Treatment Phase. Radiation
therapy will be administered using daily fractions of 2 Gy given Monday through Friday, five
consecutive days each week, followed by two days of no therapy. Radiotherapy will continue
weekly in this fashion until the total planned radiation dose of 60 to 66 Gy has been
delivered over a 6-week period. The toxicology studies of MRX-1024 were conducted exposing
animals for a maximum duration of 27 days. Therefore MRX 1024 can be administered only
during the first five weeks of radiation therapy . The sixth week of radiation therapy is
not accompanied by treatment with MRX 1024 .
Cisplatin or Carboplatin
Cisplatin will be administered intravenously on Day 1 of Week 1, Day 1 of Week 4 , and on
Day 1 of Week 7 using a dose of 100 mg per square meter of body-surface area for cisplatin
and AUC5 6 for carboplatin. On these days, the preferred sequence of treatments will be MRX
1024 Radiotherapy . This sequence should allow the MRX 1024 doses to be absorbed before
the patient potentially develops vomiting from the chemotherapy. See Section 4.6 for
guidelines regarding the use of antiemetics in conjunction with cisplatin or carboplatin
Cisplatin therapy will include pre- and post treatment hydration requirements according to
standard practices within the institution. An example of such hydration procedures follows:
Prior to receiving cisplatin, each patient must receive vigorous hydration and diuresis. A
suggested regimen is pre-hydration with a 1 liter of D5NS over 2 to 4 hours and mannitol
12.5 g intravenously bolus immediately prior to cisplatin. Then cisplatin 100 mg m2 in 500
ml NS is administered over 1 to 2 hours with an additional 1 to 1.5 liters of fluid given
post-hydration. The type, volume, and rate of fluid administration may vary based on the
patient's clinical status and ability to handle the hydration requirement.
Carboplatin therapy will also include the pre- and post-treatment hydration. For the
regimen that allows for 21 days recovery the AUC 5-6 dose will be used. The carboplatin
dose will be administered with 250 mL NS at 5 mg min mL over 30 minutes.
The dose of cisplatin given on Day 1 of Weeks 4 and 7 is to be adjusted based on the
parameters shown below. Laboratory tests used to determine the adjusted cisplatin dose are
to be obtained within 3 days prior to the scheduled cisplatin dose. For carboplatin, dose
adjustments will be based on laboratory test results obtained within 7 days prior to
Absolute neutrophil count less than 1500 µl: Cisplatin should be held if the ANC less
than 1500 µl. After the ANC recovers above this value, the cisplatin dose should be
adjusted based on the ANC nadir that was achieved following the preceding cisplatin dose, as
shown in Table 7. If the ANC has not recovered within 14 days of when the third cisplatin
dose is scheduled , the patient should complete the final Follow-Up Visit without receiving
the third dose of cisplatin. For carboplatin, the adjustment will be made if the neutrophil
count is less than 1300 mm3.
Platelet count less than 100,000 µl: Cisplatin and carboplatin should be held if the
platelet count is less than 100,000µl. After the platelet count recovers above this value,
the cisplatin dose should be adjusted based on the platelet count nadir that was achieved
following the preceding cisplatin dose, as shown in Table 7. If the platelet count has not
recovered within 14 days of when the third cisplatin dose is scheduled , the patient should
complete the final Follow Up Visit without receiving the third dose of cisplatin.
Cisplatin Dose Adjustment Based on Absolute Neutrophil Count and Platelet Count Nadirs
Following the Preceding Cisplatin Dose Nadir percentage of 100 Cisplatin Dose to Give.
Renal Toxicity: Cisplatin will not be given if the serum creatinine is greater than 1.6 mg
dL. Reduce the cisplatin dose for transient rises in serum creatinine as shown in Table 8.
Adjustments in the carboplatin dose or or delay in administration will occur if the serum
creatinine is greater than 2.0 mg dL.
Liver toxicity: An adjustment in dose or delay in administration will occur if the t. bili
is greater than 1.5 mg dL.
Cisplatin Dose Adjustment Based on Highest Serum Creatinine Value Obtained Following the
Preceding Cisplatin Dose Serum Creatinine Peak (mg dL)percentage of 100 Cisplatin Dose to
In patients whose serum creatinine does not return to less than 1.6 mg dL by the scheduled
day of cisplatin treatment , carboplatin will be substituted and continued at 3 week
intervals in lieu of cisplatin.
Neurotoxicity: Cisplatin should be discontinued if any of the following signs of
neurotoxicity occur following the first dose of cisplatin: Grade 3 hearing loss in the
speech frequency range, Grade 3 myopathy, Grade 3 weakness, Grade 3 neuropathy, seizure or
paralysis . If in the Investigator's opinion, said adverse events are related solely to
cisplatin, they would not qualify as DLTs. If in the Investigator's opinion, said adverse
events may possibly be related to co-administration of MRX 1024, they would qualify as DLTs.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
safe recommended doses and dose regimen for oral MRX-1024 with concurrent chemoradiation.
Gopal Bajaj, M.D.
Johns Hopkins University
United States: Institutional Review Board