The purpose of this study is to find the answers to the following research questions:1. What are the side effects of the combination of BAY 80-6946 and BAY 86-9766 when given together at different dose levels?2. What dose level of BAY 80-6946 and…
ID
Source
Brief title
Condition
- Other condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Health condition
gevorderde kanker
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary variables being evaluated include, safety, tolerability,
pharmacokinetics and recommended Phase II dose for the combination of BAY
80-6946 and BAY 86-9766. (protocol page 47)
Secondary outcome
Not applicable
Background summary
Phase I studies with BAY 80-6946 and BAY 86-9766 have been conducted (and are
currently ongoing) using these study drugs in a monotherapy setting. The
rationale for conducting this study is that the majority of cancers exhibit
increased signaling through either the RAS/RAF/MEK/ERK (MAPK) or the
PI3/AKT/mTOR pathway, or both. In the past decade, numerous small molecule
agents have been developed which inhibit signaling proteins in either pathway,
but the presence of feedback loops and crosstalk between the two pathways poses
a difficult barrier to the successful use of these drugs. One approach to this
problem is to use two agents, one an inhibitor of the MAPK pathway, BAY 86-9766
and the other an inhibitor of the PI3K pathway, BAY 80-6946.
Study objective
The purpose of this study is to find the answers to the following research
questions:
1. What are the side effects of the combination of BAY 80-6946 and BAY 86-9766
when given together at different dose levels?
2. What dose level of BAY 80-6946 and BAY 86-9766 should be tested in future
clinical research studies?
3. How much BAY 80-6946 is in the blood at specific times after administration
and does adding BAY 86-9766 have an affect?
4. How much BAY 86-9766 is in the blood at specific times after administration
and does adding BAY 80-6946 have an affect?
5. Does the combination of BAY 86-9766 and BAY 80-6946 have an effect on tumors?
6. Are there specific biomarkers that might be able to explain why some
patients respond to treatment and others do not?
Study design
Study 12876 is a Phase Ib, open-label, dose-escalation study of the combination
of BAY 80-6946 (PI3K inhibitor) and BAY 86 -9766 (allosteric MEK inhibitor) in
subjects with advanced cancer.
Intervention
Treatment on this study will follow a 4-week schedule and each 4-week period is
known as a *cycle*. Patients will be taking different dose strengths of each
drug depending on when they start treatment and what side effects have been
seen so far during the study.
The first drug is called BAY 80-6946. This drug is given as an IV infusion.
You will receive treatment on days 1, 8 and 15 of each cycle. Some patients
will also receive the drug on Day 22 of each cycle. If you are treated at the
lowest dose level and do not have bad side effects, and the patients at the
next highest dose level do not have serious side effects, your dose may be
increased. However, if you have bad side effects, your dose of BAY 80-6946 may
also be lowered at future visits.
The second drug is called BAY 86-9766. This drug is given by mouth. You will
start taking this drug on Day 4 of your first cycle and will take it twice a
day, either at home or in the clinic. You will be asked to keep a record of
what time and how many pills you take each day. Your dose of BAY 86-9766 will
not increase during the study, but may be lowered if you have bad side effects.
Some patients will be assigned to a schedule where they take the drug for 4
days (twice a day) and then do not take it for the next 3 days before starting
again for 4 days. If you are assigned to this schedule, you will begin taking
the drug on Day 6 of your first cycle.
Please see protocol Table 4-1: Dose escalation scheme page 42
Study burden and risks
The patient will visit the hospital minimum 10 times. In the first cycle, this
will be on day 1, 8, 15 and 22 where the patient will receive an IV with BAY
80-6946 (time: +/- 1h) with the accompanied standard procedures: blood test,
urine sample, physical exam. On Day 1, 14 and 15, the patient will spend 12h
minimum in the hospital for blood sampling. The patient will receive a morning
dose of BAY 86-9766 day 4, 8, 14 and 22 after blood sampling.
During the cycle 2, day 1: Concomitant medical review, full physical exam,
blood tests, urine sampling, ECG and MUGA-scans, ophthalmologic exam, IV with
BAY 80-6949 (time: +/- 1h), blood pressure measurement, morning dose of
BAY89-9766. On day 8 and 15: brief physical exam, blood tests, IV with BAY
80-6946 (time: +/-1h), blood pressure measurement, morning dose of BAY 86-9766.
Day 22: scans are made to assess the affliction, morning dose BAY 86-9766, IV
with BAY 80-6946 (time= +/- 1h)
Patients in cohorts 2A, 2B, 2C and the expansion cohorts, will have a FDG-PET
scan during the screening and on day 22 of Cyclus 1. Patients in the expansion
cohorts will also have a paired tumor biopsy during the screening and day 17 of
Cyclus 1.
The patient will have a risk on side effects of both experimental drugs (BAY
80-6946 and BAY 86-9766). For an extensive description, see section E9 in this
ABR-form
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Age
Inclusion criteria
- The informed consent must be signed before any study specific tests or procedures are initiated
- Subjects, at least 18 years of age, with incurable and refractory advanced or metastatic solid tumors that have progressed on or failed to respond to therapies known to provide clinical benefit
- Histological or cytological documentation of non-hematologic, malignant solid tumor, excluding primary brain or spinal tumors, with no current involvement in the central nervous system. Subjects who have brain metastases that have been treated and have been stable for > 3 months may be included in the study
- At least one measurable lesion or evaluable disease, as per RECIST 1.1
- ECOG Performance Status of 0 or 1
- Life expectancy of at least 12 weeks
- LVEF >= LLN (Lower Limit of Normal) for the Institution
- Women of childbearing age and men enrolled in this study must use adequate birth control measures prior to, during the course of the study and 30 days after the last administration of either BAY 80-6946 or BAY 86-9766. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal, or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms for subjects or their partners is required unless the woman has had a hysterectomy
- ALT and AST <= 2.5 x ULN (<= 5 x ULN for subjects with liver involvement of their cancer)
- Total bilirubin <= 1.5 x ULN
- Serum creatinine <= 1.5 x ULN
- PT-INR/PTT < 1.5 x upper limit of normal (Subjects who are being therapeutically
anti-coagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists).Low-dose aspirin is permitted (<= 100 mg daily)
- Adequate bone marrow function as assessed by the following:
- Hemoglobin >= 9.0 g/dL (transfusion permitted)
- Absolute neutrophil count (ANC) >= 1,500/mm3
- Platelet count >= 100,000/mm3
- Ability to understand and follow study-related instructions
- Only for subjects enrolled into the expansion cohort(s): Presence of a tumor mutation in one or more of the following genes: KRAS, NRAS, BRAF, or PI3KCA
Exclusion criteria
• Ability to understand andfollow study related instructions;Subjects are to be excluded from the study if they display any of the following criteria:;•History of Retinal Vein Occlusion or eye exam showing risk factor;•History of cardiac disease congestive heart failure(CHF)>NYHA Class II; active coronary artery disease, myocardial infarction within 6 months prior to study entry; new onset angina within 3 months prior to study entry or unstable angina or ventricular cardiac arrhythmias requiring anti-arrhythmic therapy. ;•Current diagnosis of Type 1 or 2 Diabetes Mellitus, or fasting blood glucose > 125 mg/dL, or HgBA1c > = 7.0;•Use of systemic corticosteroid medication within 2 weeks of the start of study treatment (topical or inhaled steroids are permitted). Single doses of systemic corticosteroids given as pre-medication for procedures or nonstudy drugs may be administered up to 24 hours of first dosing of BAY 80-6946 ;•Active clinically serious infections, including viral hepatitis, > Grade 2 (NCI CTCAE Version 4.0) ;•Uncontrolled seizure disorder;•Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.;•Known human immunodeficiency virus (HIV) infection;•Subjects undergoing renal dialysis;•Known bleeding diathesis;•Ongoing substance abuse, medical, psychological or social conditions that may interfere with the subject*s participation in the study or evaluation of the study results;•Pregnant or breast feeding women. Women of childbearing potential must have a negative serum or urine pregnancy test performed within 7 days before the start of treatment.;•Women of childbearing age and men enrolled in this study must use adequate birth control measures prior to, during the course of the study and 30 days after the last administration of either BAY 80-9766 or BAY 86-9766. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms for subjects or their partners is required unless the woman has had a hysterectomy.;•Use of strong inhibitors of CYP3A4, (eg, ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (eg, St. John*s Wort, rifampin) are prohibited within 2 weeks of starting study treatment and for the duration of the study.;• Known G6PD deficiency
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024082-45-NL |
| CCMO | NL36437.078.11 |