STEAM (SEQUENCING TRIPLET WITH AVASTINAND MAINTENANCE): FOLFOXIRI/BEVACIZUMAB REGIMENS (CONCURRENT AND SEQUENTIAL)VS. FOLFOX/BEVACIZUMAB IN FIRST-LINE METASTATIC COLORECTAL CANCER

Study ID
STU 112012-067

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • UT Southwestern Ambulatory Services
  • UT Southwestern University Hospital—St. Paul
  • UT Southwestern University Hospital– Zale Lipshy
  • Parkland Health & Hospital System

Contact
Tyson Dudley
214-648-7031
tyson.dudley@utsouthwestern.edu

Principal Investigator
Muhammad Beg

Summary

This will be a randomized, open-label, multicenter, phase ii study.

The trial will consist of a 21-day screening period, a treatment phase composed of a 4-month induction phase and a maintenance phase, a reinduction phase, two Safety Follow-up Visits occurring 28 ((+-) 3) days and 3 months ((+-) 7 days) after the last dose of study drugs along with a survival follow-up period. Date of the signed consent will be the start of the screening period.

The following treatment regimens (2-week cycles) are allowed during the 4-month induction phase (if the patient exhibits a good response [PR or SD] and still tolerates the regimen after 4 months, the chemotherapy can be continued at the investigator's discretion for up to an additional 2 months [following discussion with the Medical Monitor]):

arm a: Concurrent FoLFoXiRi/bevacizumab (2-week cycle):
* Bevacizumab, 5 mg/kg iV
* LV, 200 mg/m([SQuaReD] over 2 hours or as deemed appropriate by investigator
* irinotecan, 165 mg/m([SQuaReD] over 1 hour
* oxaliplatin, 85 mg/m([SQuaReD] over 2 hours
* 5-Fu, 3200 mg/m([SQuaReD] by 48-hour continuous infusion

arm B: Sequential FoLFoXiRi/bevacizumab (2-week cycle):
Patients receiving this regimen will receive alternating 1-month administrations of
FoLFoX/bevacizumab (2 x 2-week cycles [as described below in arm C]) and
FoLFiRi/bevacizumab (2 x 2-week cycles) as follows:
* Bevacizumab, 5 mg/kg iV
* LV, 400 mg/m([SQuaReD] over 2 hours or as deemed appropriate by investigator
* irinotecan, 180 mg/m([SQuaReD] iV over 1 hour
* 5-Fu bolus (400 mg/m([SQuaReD], followed by a 46-hour continuous infusion (2400 mg/m([SQuaReD])

arm C: FoLFoX/bevacizumab (2-week cycle):
* Bevacizumab, 5 mg/kg iV
* LV, 400 mg/m([SQuaReD] over 2 hours or as deemed appropriate by investigator
* oxaliplatin, 85 mg/m([SQuaReD] over 2 hours
* 5-Fu bolus (400 mg/m([SQuaReD] ), followed by a 46-hour continuous
infusion (2400 mg/m([SQuaReD])

The following treatment regimens are allowed during the maintenance phase (preferably, the investigator should choose one of the following and stay with it; switching is
allowed, however, if toxicities arise):
5-Fluorouracil/bevacizumab (2-week cycle):
* Bevacizumab, 5 mg/kg iV
* LV, 400 mg/m([SQuaReD] over 2 hours or as deemed appropriate by investigator
* 5-Fu bolus (400 mg/m([SQuaReD] ), followed by a 46-hour
continuous infusion (2400 mg/m([SQuaReD])

Capecitabine/bevacizumab (3-week cycle)
* Bevacizumab, 7.5 mg/kg iV
* Capecitabine, 1000 or 850 mg/m([SQuaReD] p.o. b.i.d. (at the investigator's discretion) on Days 1 to 14,
repeated every 3 weeks



Participant Eligibility

Inclusion Criteria
Patients must meet the following criteria for study entry:
Disease-specific inclusion criteria:
1. Histologically-confirmed CRC with at least one measurable metastatic lesion by
RECIST v1.1, that is considered unresectable at baseline.
General inclusion criteria:
2. Signed informed consent prior to initiation of any study-specific procedure
or treatment
3. Age >= 18 and <= 75 years
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
(see Appendix B) if < 71 years; ECOG status of 0 if >= 71 and <= 75 years
5. Able to comply with the protocol, including tissue and blood sampling
6. Adequate hematological function:
x Absolute neutrophil count (ANC) >= 1500 per mm3 AND
x Platelet count >= 100,000 per mm3 AND
x Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level)
7. Adequate liver function:
x Total bilirubin < 1.5 x upper limit of normal (ULN) AND
x Aspartate aminotransferase (AST) and alanine (ALT) < 2.5 x ULN in patients
without liver metastases or < 5 x ULN in patients with liver metastases
8. Adequate renal function:
x Creatinine < 2.0 x ULN, OR
x Calculated creatinine clearance according to the formula of Cockroft and
Gault >=50 mL/min
x AND
x Urine for proteinuria should be < 2+. Patients discovered to have >=2+
proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine
collection and must demonstrate < 1 g of protein in 24 hours
9. International normalized ratio (INR) <= 1.5 and activated prothrombin time (aPTT)
<= 1.5 x ULN within 7 days prior to randomization for patients not receiving anticoagulation
therapy. The use of full-dose oral or parenteral anticoagulants is
permitted as long as the INR or aPTT is within therapeutic limits (according to the
medical standard of the enrolling institution) and the patient has been on a stable
dose of anticoagulants for at least two weeks prior to the first study treatment
10. Patients with treated brain metastases are eligible for study participation. Patients
may not receive ongoing treatment with steroids at screening. Anticonvulsants
(at stable dose) are allowed. Treatment for brain metastases may be whole-brain
radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate
by the treating physician. Radiotherapy and stereotactic radiosurgery must be
completed at least 28 days prior to randomization
11. If not postmenopausal (< 12 months of amenorrhea) or surgically sterile, females
must agree to use a highly effective contraceptive method (i.e., with a failure rate of
< 1% per year, such as hormonal implants, combined oral contraceptives, or
vasectomized partner) during the treatment period and for at least 6 months after
the last dose of study drug
12. If fertile, males must agree to use a highly effective contraceptive method (i.e., with
a failure rate of < 1 % per year, such as vasectomy, sexual abstinence, or female
partner's use of hormonal implants or combined oral contraceptives) during the trial
and for a period of at least 6 months after the last dose of study drug