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Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors


Phase 2
18 Years
N/A
Not Enrolling
Both
Neoplasms

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Trial Information

Molecular Profiling-based Assignment of Cancer Therapy for Patients With Advanced Solid Tumors


Background:

-Targeted therapy based on identifying underlying genetic aberrations within the tumor is
the goal of personalized medicine. This pilot trial aims to establish whether advanced
cancer patients who have no treatment options with proven benefit, and with tumor
mutations/amplifications in one of 3 genetic pathways (DNA repair, PI3K, or RAS/RAF) are
more likely to derive clinical benefit if treated with agents targeting that pathway than if
treated with agents that do not. Each patient will be randomly assigned to receive the
recommended Phase II dose of either a study drug identified to work on their tumor's
mutation/aberrant pathway, or an agent from the complementary set not identified to work on
the mutations/amplifications of interest.

Objectives:

-Compare the response rate (CR+PR) and/or 4-month PFS for treatment with agents chosen based
on the presence of specific mutations/amplifications in patient tumors with the response
rate for treatment with agents randomly chosen from the complementary set of agents not
identified to work on the mutations/amplifications of interest.

Eligibility:

- Adult patients with histologically documented solid tumors whose disease has progressed
following at least one line of standard therapy and/or for which no standard treatment
is available that has been shown to improve survival.

- Tumor amenable to percutaneous biopsy, and willingness to undergo tumor biopsy.

Study Design:

- Patients enrolled on study will have a tumor biopsy sequenced in a CLIA-certified lab
for specific mutations/amplifications of interest: DNA repair pathways, PI3K pathway,
or RAS pathway. If such mutations are not detected, the patient will be taken off
study.

- Patients with melanoma and known BRAF V600E mutations need to have received and
progressed on specific BRAF inhibitor therapy.

- Patients with ovarian or breast cancer and BRCA mutations will not receive ABT-888
on study for the treatment of BRCA-positive tumors. They will only be eligible to
receive any of the study treatments if they have other mutations of interest.

- Patients with NSCLC should have been previously tested for the presence of EGFR
and ALK mutations, and, if detected, should have received and progressed on EGFR
or ALK TKI therapy.

- Patients in whom a mutation/amplification of interest is detected will be randomized
2:1 into Arms A or B: Arm A will receive an agent prospectively identified to target
that mutation/pathway; Arm B will receive an agent from the complementary set (not
prospectively identified to target one of their mutations/amplifications). Patients in
Arm B will be allowed to cross over at the time of disease progression to a treatment
regimen based on their mutational analysis.

- Targeted drugs will be administered at recommended Phase II doses and schedules: (1)
ABT-888 (PARP inhibitor) with temozolomide for defects in the DNA repair pathway; (2)
MK-1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathway; (3)
Everolimus (mTOR inhibitor) for mutations in the PI3K pathway; or (4) Trametinib DMSO
(MEK inhibitor) for mutations in the RAS pathway.

- Given the relative frequencies of the mutations, approximately 700 patients will need
to be enrolled to acquire 180 evaluable patients; the initial feasibility part of the
trial will be conducted in the first 60 evaluable patients, requiring enrollment of
100-150 patients.

Inclusion Criteria


- INCLUSION CRITERIA: Tumor Biopsy Sequencing

- Patients with histologically documented solid tumors whose disease has progressed
following at least one line of standard therapy and/or no standard of treatment
exists that has been shown to prolong survival.

- Patient must have tumor amenable to percutaneous biopsy and be willing to undergo a
tumor biopsy.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
greater than or equal to 20 mm with conventional techniques or as greater than or
equal to 10 mm with spiral CT scan.

- Patients with bone metastases or hypercalcemia on intravenous bisphosphonate
treatment are eligible to participate and may continue this treatment.

- Age greater than or equal 18 years. Children are excluded from this study, but may be
eligible for future pediatric trials.

- Karnofsky performance status greater than or equal 70

- Life expectancy greater thatn 3 months.

- Patients must have adequate organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500 per microliters (mcL)

- platelets greater than or equal to 100,000 per microliters (mcL)

- total bilirubin less than 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
normal

- creatinine less than 1.5 times institutional upper limit of normal

OR

- creatinine clearance greater than or equal to 60 mL/min for patients with creatinine
levels greater than or equal to 1.5 times institutional upper limit of normal.

- PTT less than or equal to 40 seconds unless due to lupus coagulant

- The effects of these targeted agents on the developing human fetus are unknown.
For this reason, women of childbearing potential and men must agree to use
adequate contraception prior to study entry, for the duration of study
participation, and for 3 months after completion of study. Because there may be
a risk for adverse events in nursing infants secondary to treatment of the
mother with these agents, breastfeeding should be discontinued while the patient
is on this trial and for 30 days following last dose of study drug.

- Patients with history of CNS metastases who have received treatment and who
either have not had seizures or have been on stable doses of anti-seizure
medicine and had no seizures for 2 weeks will be eligible. Enzyme-inducing
anticonvulsants are contraindicated.

- Ability to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA: Tumor Biopsy Sequencing

- Women who are pregnant or breastfeeding.

- Patients who are receiving any other investigational agents.

- Patients with uncontrolled intercurrent illness including, but not limited to
psychiatric illness/social situations that would limit compliance with study
requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, myocardial infarction in the past 6 months, or left ventricular ejection
fraction (LVEF) less than or equal to the institutional lower limit of normal (by
ECHO or MUGA), invasive fungal infections, or active hepatitis B infection are not
eligible to participate. Testing for hepatitis B or other infections

for eligibility will be performed only if clinically indicated.

- Patients who have had prior treatment with any PARP inhibitor are ineligible to
receive treatment with a PARP inhibitor on this study.

- Patients who have received prior temozolomide should not be excluded solely because
of receiving prior temozolomide, unless it was in combination with a PARP inhibitor.
Such patients will not be offered ABT-888 with temozolomide, but are eligible to
receive other treatment regimens on study based on identified genetic mutations.

- Patients with gastrointestinal conditions that might predispose for drug
intolerability or poor drug absorption (e.g., inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption,
malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with
ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel
obstruction are also excluded, as are any patients who cannot swallow tablets or
capsules whole. Tablets or capsules must not be crushed or chewed; nasogastric or
G-tube administration is not allowed.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for PK interactions.

- Patients who require use of coumarin-derivative anticoagulants such as warfarin are
excluded. Low molecular weight heparin is permitted for prophylactic or therapeutic
use. Only patients who meet the screening criteria and have a tumor biopsy determined
to have one of the specific mutations/amplifications of interest will be eligible to
participate in the treatment part of this protocol.

INCLUSION CRITERIA: Treatment

- Patient must have predefined targeted mutation in tumor biopsy.

- Patients with histologically documented solid tumors whose disease has progressed
following at least one line of standard therapy or for which no standard therapy
exists that has been shown to prolong survival.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
greater than or equal to 20 mm with conventional techniques or as greater than or
equal 10 mm with spiral CT scan.

- Any prior therapy, radiotherapy, or major surgery must have been completed greater
than or equal 3 weeks (greater than 6 weeks for nitrosoureas or mitomycin C) prior to
enrollment on protocol, and the participant must have recovered to eligibility levels
from prior toxicity. RFA of localized lesions should have been performed greater than
or equal 2 weeks prior to enrollment.

- Patients who have had prior treatment with any of the other investigational agents on
this protocol are eligible but will not receive the same investigational agent;
instead, patients will receive an investigational agent prospectively identified to
work on a different target in their tumor's mutation/aberrant pathway.

- Patients with bone metastases or hypercalcemia on intravenous bisphosphonate
treatment are eligible to participate and may continue this treatment.

- Age greater than or equal 18 years. Because no dosing or adverse event data are
currently available on the use of study investigational agents in patients less than
18 years of age, children are excluded from this study, but may be eligible for
future pediatric trials.

- Karnofsky performance status greater than or equal 70%.

- Life expectancy greater than 3 months.

- Patients must have adequate organ and marrow function as defined below:

- absolute neutrophil count greater than or equal 1,500 per microliters (mcL)

- platelets greater than or equal 100,000 per microliters (mcL)

- total bilirubin less than 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 3 times institutional upper limit of
normal

- creatinine less than 1.5 times institutional upper limit of normal

OR

- creatinine clearance greater than or equal 60 mL/min for patients with creatinine
levels greater than or equal 1.5 times institutional upper limit of normal.

- The effects of these targeted agents on the developing human fetus are unknown.
For this reason, women of childbearing potential and men must agree to use
adequate contraception (abstinence; female use of hormonal methods, or barrier
methods of birth control; male use of a condom) prior to study entry, for the
duration of study participation, and for 3 months after completion of study.
Because there may be a risk for adverse events in nursing infants secondary to
treatment of the mother with these agents, breastfeeding should be discontinued
while the patient is on this trial and for 30 days following last dose of study
drug.

- Patients with melanoma and known BRAF V600E mutations must have received and
progressed on specific BRAF inhibitor therapy.

- Patients with NSCLC must have previously been tested for the presence of EGFR
mutations, and, if detected, should have received and progressed on EGFR
tyrosine kinase inhibitor (TKI) therapy.

- Patients with ovarian or breast cancer and BRCA mutations will not receive ABT-
888 on study. There is already some evidence of clinical benefit of treating
patients with known BRCA-positive tumors with PARP inhibitors. Such patients can
pursue therapy on trials specifically testing PARP inhibitors in BRCApositive
patients with advanced tumors. If these patients have other mutations of
interest as defined in the protocol, they will be eligible to receive agents
based on that mutation.

- Patients who have poorly controlled diabetes (defined as fasting blood glucose
of greater than 160 mg/dL (CTCAE Grade greater than or equal to 2) and HgA1c
greater than 8%) are ineligible to receive treatment with everolimus on study.

- Patients with a known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to Trametinib DMSO, its excipients, or
DMSO, are ineligible to receive treatment with Trametinib DMSO.

- Patients with a history or current evidence/risk of retinal vein occlusion (RVO)
or central serous retinopathy (CSR) or predisposing factors to RVO or CSR (e.g.,
uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such
as hypertension, diabetes mellitus, or history of hyperviscosity or
hypercoagulability syndromes), are ineligible to receive treatment with
Trametinib DMSO. Visible retinal pathology (as assessed by ophthalmic exam) that
is considered a risk factor for RVO or CSR includes evidence of new optic disc
cupping or new visual field defects, or intraocular pressure greater than 21 mm
Hg.

- Patients with a history of seizures are not eligible to receive ABT-888.
Patients with brain metastatic disease must have remained stable for greater
than 3 months and be off steroid treatment to be eligible to receive ABT-888.

- Patients who have received prior carboplatin or MK-1775 would not be excluded
unless the two drugs were administered in combination. Patients who have
received prior carboplatin in combination with MK 1775 would still be eligible
to receive other study treatment regimens based on identified genetic
mutation(s), other than carboplatin plus MK-1775.

- Patients who have had prior treatment with any PARP inhibitor are ineligible to
receive treatment with a PARP inhibitor on this study. Patients who have
received prior temozolomide should not be excluded solely because of receiving
prior temozolomide, unless it was in combination with a PARP inhibitor. Patients
who have received temozolomide with a PARP inhibitor in the past are eligible to
participate but will not receive ABT-888 with temozolomide on study. Such
patients are eligible to receive other treatment regimens on study based on
identified genetic mutations.

- Patients who have received prior everolimus or other mTOR inhibitors would not
be eligible to receive everolimus on study. If these patients have mutations of
interest in pathways other than the pI3K pathway as defined in the protocol,
they will be eligible to receive agents based on that mutation.

- Patients who have received prior MEK inhibitors would not be eligible to receive
trametinib DMSO on study. If these patients have mutations of interest in
pathways other than the RAS pathway as defined in the protocol, they will be
eligible to receive agents based on that mutation.

- Patients with a history of interstitial lung disease or pneumonitis will not be
assigned treatment with everolimus.

EXCLUSION CRITERIA: Treatment

- Women who are pregnant or breastfeeding.

- Patients who are receiving any other investigational agents.

- Patients with active brain metastases or carcinomatous meningitis are excluded from
this clinical trial. Patients whose brain metastatic disease status has remained
stable for greater than 3 months and are off steroid treatment are eligible to
receive ABT-888; patients whose brain metastatic disease status has remained stable
for greater than or equal to 4 weeks following treatment of the brain metastases are
eligible for other study agents. Patients who have a history of seizures are not
eligible to receive ABT- 888, but patients who have either not had seizures or who
have been on stable doses of anti-seizure medicine and had no seizures for 1 month
will be eligible for other study agents. Enzyme-inducing anticonvulsants are
contraindicated.

- Patients with uncontrolled intercurrent illness including, but not limited to
psychiatric illness/social situations that would limit compliance with study
requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, myocardial infarction in the past 6 months, or left ventricular ejection
fraction (LVEF) less than or equal to the institutional lower limit of normal (by
ECHO or MUGA), invasive fungal infections, or active hepatitis B infection are not
eligible to participate. Testing for hepatitis B or other infections for eligibility
will be performed only if clinically indicated.

- Patients with gastrointestinal conditions that might predispose for drug
intolerability or poor drug absorption (e.g., inability to take oral medication or a
requirement for IV alimentation, prior surgical procedures affecting absorption,
malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with
ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel
obstruction are also excluded, as are any patients who cannot swallow tablets or
capsules whole. Tab...

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind, Primary Purpose: Treatment

Outcome Measure:

Compare response rate and/or 4-month PFS for agents chosen based on presence of specific tumor mutations/amplifications with response rate for agents randomly chosen from complementary set of agents not identified to target mutations of interest...

Outcome Time Frame:

1.5 - 3 years

Safety Issue:

Yes

Principal Investigator

Shivaani Kummar, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

130105

NCT ID:

NCT01827384

Start Date:

March 2013

Completion Date:

March 2017

Related Keywords:

  • Neoplasms
  • Targeted Therapy
  • Genetic Sequencing
  • Advanced Cancer
  • Pharmacodynamics
  • Tumor Mutations
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892