Primary:Dual-agent dose escalation part (Part 1):• To determine the maximum tolerated dose of oral, daily (qd) BEZ235 in combination with paclitaxel, qw in patients with advanced solid tumors(MTD1, Arm 1).• To determine the maximum tolerated dose of…
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Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
- Breast disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence of dose-limiting toxicities (DLTs) in patients with concomitant
administration of BEZ235 or BKM120 and paclitaxel (± trastuzumab).
Secondary outcome
• Safety and tolerability: type, frequency, and severity of adverse events
(AEs), adverse drug reactions, and laboratory abnormalities per
CTCAEv4.0 (Common Toxicity Criteria for Adverse Events, version 4.0)
• Pharmacokinetics:
• Time versus plasma concentration profiles of paclitaxel as single agent and
in combination treatment
• Time versus plasma concentration profiles of BEZ235 and BKM120 in combination
treatment
• Trastuzumab trough levels
• Basic PK parameters for paclitaxel, BEZ235, and BKM120 including, but not
limited to, AUCtlast, AUCinf, AUC0-24, Cmax, tmax, terminal t1/2, and other PK
parameters if deemed appropriate
• Overall response per RECIST
Exploratory endpoints :
• Antitumor activity: standard circulating tumor markers
• Phospho-S6 ribosomal protein (p-S6) in skin
• Increase in tumor apoptotic markers (circulating markers)
• PI3K pathway analysis (PIK3CA mutation, PTEN alteration in tumors)
• New biomarkers will be integrated if developed during this trial and
considered appropriate for judgment of efficacy and safety
• Basic PK parameters for the paclitaxel metabolites including, but not limited
to, AUC0-tlast, AUC0-inf, AUC0-24, Cmax, tmax, terminal t1/2, and other PK
parameters if deemed appropriate
Background summary
Although the inclusion of paclitaxel and trastuzumab in the armamentarium of
cancer treatments has significantly improved the treatment outcome for many
patients, a considerable number of tumors are insensitive to treatment with
paclitaxel and/or trastuzumab a priori or eventually develop treatment
resistance during the course of the treatment. While the exact mechanisms
underlying the development of treatment resistance remain obscure, it is of
note that activation of the PI3K pathway is believed to play an important role.
In addition, it has been shown that concomitant inhibition of the PI3K pathway
enhances the efficacy of paclitaxel and reverts resistance towards
HER2-targeted treatments.
BKM120 is a potent and highly specific oral pan-class I phosphatidylinositol-3-
kinase (PI3K) inhibitor, currently under investigation in a first-in-man study
in patients with advanced solid tumors (wild type and PIK3CA-mutated).
Consistent, dose-dependent pharmacodynamic activity has been demonstrated and
clear signs of anti-tumor activity have been seen with BKM120.
BEZ235 is a pan-class I PI3K and mTORC1/C2 inhibitor under investigation in a
first-in-man study. Clinical data shows that BEZ235 treatment is well
tolerated, induces dose-dependent pathway inhibition in tissues, and results in
anti-tumor activity, particularly in patients with PI3K pathway deregulated
cancers.
Collectively, the available data suggests that BKM120 and BEZ235 may not only
enhance the antitumor activity of the paclitaxel and paclitaxel/trastuzumab
regimens, but could potentially delay and/or revert treatment resistance.
Study objective
Primary:
Dual-agent dose escalation part (Part 1):
• To determine the maximum tolerated dose of oral, daily (qd) BEZ235 in
combination with paclitaxel, qw in patients with advanced solid tumors
(MTD1, Arm 1).
• To determine the maximum tolerated dose of oral BKM120, qd in combination
with paclitaxel, qw in patients with advanced solid tumors
(MTD2, Arm 2).
Triple-agent dose combination part (Part 2):
• To determine the maximum tolerated dose of oral BEZ235, qd in combination
with paclitaxel/trastuzumab, qw in patients with HER2+
metastatic breast cancer (MTD3, Arm 3).
• To determine the maximum tolerated dose of oral BKM120, qd in combination
with paclitaxel/trastuzumab, qw in patients with HER2+
metastatic breast cancer (MTD4, Arm 4).
Secondary:
• To assess the safety and tolerability, including acute and chronic
toxicities, of the dual and triple combinations evaluated.
• To characterize the single-dose pharmacokinetics of single-agent paclitaxel
on Day 1
• To characterize the multiple-dose pharmacokinetics of BEZ235/BKM120 qd and
paclitaxel qw when given in combination (Day 8 and 22)
• To characterize exposure to trastuzumab (trough levels)
• To assess the preliminary anti-tumor activity of the different treatment
regimens
Exploratory:
• To assess PI3K pathway inhibition in skin biopsies
• To assess treatment-related changes in circulating markers of biologic effect
(antitumor effect, safety)
• To assess the mutational status of the tumor (PIK3CA, PTEN)
• To evaluate the pharmacokinetics of the 3 paclitaxel metabolites of interest:
6a-hydroxypaclitaxel (cytochrome P450 [CYP] 2C8), 3'-p-hydroxypaclitaxel
(CYP3A4), and 6α and 3'-p- dihydroxypaclitaxel
Study design
This is a multi-center phase Ib, open-label, 4-arm, dose-finding study
consisting of two parts:
Part 1 (dual-agent dose escalation):
• Arm 1 assesses the combination of BEZ235 with weekly paclitaxel
• Arm 2 assesses the combination of BKM120 with weekly paclitaxel
Part 2 (triple-agent dose combination):
• Arm 3 assesses the combination of BEZ235 with weekly paclitaxel/trastuzumab
• Arm 4 assesses the combination of BKM120 with weekly paclitaxel/trastuzumab
Dual-agent dose escalation part:
The first part will determine the maximum tolerated dose of the combination of
weekly paclitaxel given with either daily BEZ235 (MTD1) or daily BKM120 (MTD2).
• Arm 1 : Paclitaxel qw + BEZ235 qd
• Arm 2 : Paclitaxel qw + BKM120 qd
During this dual-agent dose escalation part of the study the maximum tolerated
doses in each arm will be determined based on dose-limiting
toxicities (DLTs) occurring during the first cycle of treatment.
In part 1, the initial cohorts will consist of 1 patient. As soon as
non-hematologic toxicities of CTCAE grade >= 2 are observed for which a
relationship with the study drug cannot be ruled out, the cohort will be
expanded to 3 patients (see Section 10).
It is anticipated that at least 15 patients per arm will be needed to define
the MTDs in the dual-agent dose escalation part.
Triple-agent dose combination part:
The objective of the triple-agent dose combination part is to evaluate the
safety and tolerability of the following combinations:
• Arm 3: BEZ235 qd, paclitaxel and trastuzumab qw
• Arm 4: BKM120 qd, paclitaxel and trastuzumab qw.
The starting doses for BEZ235, BKM120, and paclitaxel in the triple-agent dose
escalation part will be determined on the basis of data from the dualagent dose
escalation part.
A minimum of six patients per arm will be necessary to declare the MTDs of the
triple-agent combinations.
Intervention
• BEZ235: starting dose 400 mg/day
• BKM120: starting dose 40 mg/day
• Paclitaxel: 70 mg/m2
• Trastuzumab: 2 mg/kg (if applicable starting dose of 4mg/kg)
Arm 1: Paclitaxel + BEZ235
Arm 2: Paclitaxel + BKM120
Arm 3: Paclitaxel + trastuzumab + BEZ235
Arm 4: Paclitaxel + trastuzumab + BKM120
Study burden and risks
Study assessments will be performed at prescreening, baseline, C1D1, C1D8,
C1D15, C1D22, C2D1, C2D8, C2D15, C2D22 and CXD1, CXD8, CxD15, CxD22 of every
consecutive cycle. Treatment duration will continue until disease progression
(defined by RECIST), unacceptable toxicity, patient withdrawal, death,
investigators decision or discontinuation from the study for any other reason,
whereupon all patients will complete the End of Treatment visit. The final
Follow up Visit should be performed at least 28 days after end of study to
collect safety, further anticancer therapy and survival information.
Please refer to Protocol table 7-1, page 68.
The main side effects and observations seen in studies with BEZ235 are:
• fatigue
• skin rash
• nausea
• vomiting
• diarrhea
• thrombocytopenia
Please refer to Protocol section 1.2.4. pages 31 to 32
The main side effects and observations seen in studies with BKM120 are:
• anorexia
• nausea
• rash
• constipation
• diarrhea
• hyperglycemia
• fatigiue/asthenia
• vomiting
• anxiety
• mood disorders
• transaminase increase
• pruritus
• GI disorders
Please refer to Protocol section 1.3.4. pages 34 to 36
Anticipated risks and safety consideration of the drug combination:
Preliminary clinical data available from ongoing studies with BKM120 and BEZ235
do not suggest a major overlap in toxicities with paclitaxel. However, there is
the possibility that certain toxicities may be exacerbated or seen with a
greater frequency.
In the case of the combinations BEZ235/paclitaxel or
BEZ235/paclitaxel/trastuzumab, special attention should be paid to the
following toxicities:
• Fatigue, skin rash, thrombocytopenia, nausea/vomiting/diarrhea, disturbances
of the coagulation system, disturbances of cardiac function, and disturbances
of the vital signs.
In case of combination treatment with BKM120/paclitaxel and BKM120/
paclitaxel/trastuzumab, special attention should be paid to the following
toxicities:
• Neuropsychiatric disorders, skin rash, hyperglycemia,
nausea/vomiting/diarrhea, fatigue, disturbances of cardiac function, and
disturbances of the vital signs.
The potential for clinically significant drug-drug interactions with the
proposed combination of paclitaxel with BEZ235 or BKM120 is considered low.
Conversely, data from preclinical studies showed that both BEZ235 and BKM120
can induce significant myelosuppression.
Hence, combination treatment with paclitaxel and BEZ235 or BKM120 may be
associated with a higher risk of bone marrow toxicity.
Toxicity due to the use of paclitaxel (refer to SMPC of paclitaxel)
Toxicity due to the use of trastuzumab (refer to SMPC of trastuzumab)
Other risks:
Taking blood and biopsies may cause pain, bleeding, and/or bruising.
Patients will be exposed to radiation (CT-scan, and X-rays). The radiation
exposure will not exceed the maximum ranges that are set within the
Netherlands.
Use of contrast when making a CT-scan may cause an allergic reaction.
Raapopseweg 1
6824 DP Arnhem
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Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
Dual-agent part:
• Patients with metastatic or locally advanced solid tumors eligible for weekly paclitaxel;Triple-agent part:
• HER2+ metastatic or locally advanced breast cancer patients eligible for weekly paclitaxel and trastuzumab;For both parts:
• WHO performance status <= 2
• Absolute neutrophil count >= 1.5 ×109/L
• Hemoglobin >= 10g/dL = 6.2 mmol/L
• Platelets >= 100 ×109/L
• Serum albumin >= 3.0 g/dL
• AST/SGOT and ALT/SGPT <= upper limit of normal (ULN) or <=2.5 × ULN if liver metastases are present
• Serum bilirubin <= ULN or <= 1.5 ×ULN if liver metastases are present
• Serum creatinine <= 1.5 × ULN or 24-hour creatinine clearance >= 50 mL/min
• Partial thromboplastin time (PTT) <= 1.5 × ULN
• Prothrombin time (PT)/international normalized ratio (INR) <=1.5 × ULN
• New York Heart Association (NYHA) grade <= 2
• Left ventricular ejection fraction (LVEF) >= 50% (MUGA scan or echocardiogram)
• QTc interval <= 460 ms on screening ECG
• Fasting plasma glucose <= 140 mg/dL (7.8 mmol/L)
• Recovery from all reversible adverse events of previous anticancer therapies to grade 1, except for alopecia and peripheral neuropathy
Exclusion criteria
• Patients with primary central nervous system (CNS) tumor or CNS tumor involvement. However, patients with a metastatic CNS lesion may participate in this trial, if the patient is > 4 weeks from therapy completion, clinically stable and not receiving enzyme-inducing antiepileptic drugs or corticosteroid therapy
• Patients who have received prior systemic anticancer therapy within the following time frames
- Chemotherapy <= 3 weeks before study treatment (6 weeks for nitrosoureas)
- Biological therapy <= 4 weeks before study treatment, except trastuzumab
- Investigational drug <= 4 weeks before study treatment
• Major surgery <= 4 weeks before study treatment
• Chronic treatment with corticosteroids or other immunosuppressive agents
• Uncontrolled diabetes mellitus
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
• Treatment with agents that are metabolized solely by CYP3A and/or have a narrow therapeutic window or are strong inhibitors or inducers of CYP3A or CYP2C8.
• QT-prolonging medication known to have a risk to induce Torsades de Pointes
• Radiotherapy <= 4 weeks before starting study drug
• Prior treatment with PI3K inhibitors
• Known hypersensitivity to paclitaxel, polyethoxylated castor oil (Cremophor EL) or excipients of trastuzumab, BEZ235, or BKM120
• Patients with known human immunodeficiency virus (HIV)
• Active or history of major depressive episode, bipolar disorder, obsessive -compulsive disorder, schizophrenia, history of suicide attempt or ideation, or homicide
• Women of child-bearing potential and male patients must use adequate contraception methods throughout the study and for 12 weeks after study drug discontinuation
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 | EUCTR2010-022331-11-NL |
| CCMO | NL34474.031.10 |