Nanoparticle Albumin-Bound Rapamycin in Treating Patients With Advanced Cancer With mTOR Mutations

PRIMARY OBJECTIVES:

I. To investigate efficacy of groups of patients defined by disease type, genomic aberration
and treatment regimen.

II. To assess the confirmed response rate of nanoparticle albumin-bound rapamycin
(nab-rapamycin) in mTOR aberrant advanced cancers. (Sub-protocol Arm A)

SECONDARY OBJECTIVES:

I. To estimate other clinical outcomes (e.g., progression-free and overall survival) of
groups of patients defined by disease type, genomic aberration and treatment regimen.

II. To describe the adverse event profile of each regimen. III. To assess the clinical
benefit rate of nab-rapamycin in mTOR aberrant advanced cancers. (Sub-protocol Arm A).

IV. To estimate progression-free survival (specifically at 6 months) and overall survival of
these patients. (Sub-protocol Arm A) V. To estimate the adverse event profile of
nab-rapamycin. (Sub-protocol Arm A)

TERTIARY OBJECTIVES:

I. To describe patient health-related quality of life (HRQOL) and symptoms using the European
Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core
(QLQ-C)30 in groups of patients defined by disease type and/or treatment regimen and to
correlative HRQOL/symptoms with genomic markers.

II. To assess the rate of individual mTOR pathway aberrations and assess the association
between individual mTOR pathway aberrations and clinical outcome both across disease
indications and within disease indications. (Sub-protocol Arm A)

OUTLINE:

Patients receive nanoparticle albumin-bound rapamycin intravenously (IV) over 30 minutes on
days 1 and 8. Treatment repeats every 21 days for 24 weeks in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Histologic proof of cancer which is now not amenable to curative standard treatment
options

- Patient must have received at least 1 prior standard therapy for their disease

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

- Ability to provide informed written consent

- Willing to return to enrolling institution for follow-up (active monitoring phase of
the study); Note: During the active monitoring phase of a study (i.e., active
treatment), participants must be willing to return to the consenting institution for
follow-up

- Life expectancy >= 84 days (3 months)

- Identification of a drug target/targets through molecular profiling performed as a
part of routine clinical care and treatment recommendation by the Mayo Clinic Genomics
Tumor Board (GTB); NOTE: If profile matches more than 1 treatment arm, final decision
for treatment arm assignment to be made by patients treating physician; it will be
required for the genomic aberration to be identified through a test in a Clinical
Laboratory Improvement Amendments (CLIA) workflow; assays used will range from single
gene abnormalities (e.g. fluorescent in situ hybridization [FISH] for human epidermal
growth factor receptor 2 [ERBB2] amplifications) to next generation sequencing based
gene panels (Foundation One®) to more comprehensive assays such as whole exome
sequencing; the Mayo Clinic GTB will serve as the centralized point of data synthesis
to allow for assessment of molecular profiling accomplished through a heterogeneous
array of tests

- Date of Mayo Clinic Genomics Tumor Board review =< 3 months prior to registration

- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version
(v)1.1 criteria (for solid tumors) or equivalent criteria (for patients with non-solid
tumor malignancies)

- Patient meets all sub-protocol specific criteria of each applicable sub-protocol

- Ability to complete questionnaire(s) by themselves or with assistance

- SUB-PROTOCOL AIM A: Histological confirmation of renal cell carcinoma, head and neck
cancer, endometrial cancer, breast cancer, ovarian cancer, prostate cancer, squamous
cell cervical or uterine cancer, or bladder cancer

- SUB-PROTOCOL AIM A: Confirmation of advanced cancer with mTOR pathway aberrations as
determined through routine clinical care using pathway aberrations performed in a CLIA
certified laboratory; cancer genomic profiling tests incorporating next generation
sequencing from archival formalin-fixed paraffin-embedded tissue (FFPE) are validated
with sensitivities and specificities of 99% and 99%, respectively; in the assay,
hybrid-capture-selected deoxyribonucleic acid (DNA) libraries are sequenced to depths
targeting > 500 × coverage by non-polymerase chain reaction (PCR) duplicate read
pairs, with > 99% of exons at coverage > 100 ×); multiplatform profiling may include
immunohistochemistry and in situ hybridization methods with previously established
negative/positive cutoffs performed in a CLIA certified lab; at least one pathway
aberration must be identified; these must be confirmed in a CLIA certified lab; the
potential mTOR aberrations that could be identified are listed below, please note that
this list is not all inclusive; if a CLIA validated report lists an mTOR pathway
inhibitor as a target drug for a genetic aberration, then it can be considered
eligible for the purposes of this study; v-akt murine thymoma viral oncogene homolog 1
(AKT1), MTOR, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
(PIK3CA), tuberous sclerosis (TSC)1, TSC2, retrovirus-associated DNA sequence (Ras)
homolog enriched in brain (RHEB), serine/threonine kinase 11 (STK11), neurofibromin
(NF)1/2

- SUB-PROTOCOL AIM A: Absolute neutrophil count (ANC) >= 1500/mm^3

- SUB-PROTOCOL AIM A: Platelet count >= 100,000/mm^3

- SUB-PROTOCOL AIM A: Hemoglobin >= 9.0 g/dL

- SUB-PROTOCOL AIM A: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

- SUB-PROTOCOL AIM A: Aspartate transaminase (AST); alanine aminotransferase (ALT) =<
1.5 x ULN; NOTE: if subject has tumor involvement in the liver =< 5 X ULN

- SUB-PROTOCOL AIM A: Serum cholesterol =< 350 mg/dL

- SUB-PROTOCOL AIM A: Serum triglyceride =< 300 mg/dL

- SUB-PROTOCOL AIM A: Serum creatinine =< 1.5 x ULN

- SUB-PROTOCOL AIM A: Previously treated patients who have failed, unable to tolerate,
or refused other available active therapies

- SUB-PROTOCOL AIM A: Women of child-bearing potential, defined as sexually mature women
who have not undergone a hysterectomy or who have not been naturally postmenopausal
for at least 12 consecutive months (e.g., who has had menses any time in the preceding
12 consecutive months), must have a negative serum pregnancy test =< 14 days prior to
registration and must use two forms of highly effective contraception (also applicable
to their partners who are biologically able to conceive)

- SUB-PROTOCOL AIM A: Adequate coagulation function as defined by either of the
following criteria:

- International normalized ratio (INR) =< 1.5 x ULN

- For subjects receiving warfarin or low molecular weight heparin (LMWH), the
subjects must, in the investigator's opinion, be clinically stable with no
evidence of active bleeding while receiving anticoagulant therapy; the INR for
these patients may exceed 1.5 x ULN if that is the goal of the anticoagulant
therapy

Exclusion Criteria:

- Uncontrolled intercurrent illness including, but not limited to: ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Failure to fully recover from acute, reversible effects of prior chemotherapy (other
anti-neoplastic therapy) and radiation therapy to adverse event severity of =< grade 1

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the
prescribed regimens

- SUB-PROTOCOL AIM A: Any of the following:

- Pregnant women

- Nursing women

- Women of child-bearing potential, who are biologically able to conceive, or men
who are able to father a child, not employing two forms of highly effective
contraception

- Highly effective contraception (e.g., male condom with spermicide, diaphragm
with spermicide, intra-uterine device, and total abstinence) must be used by
both sexes during the study and must be continued for 6 months after the end
of study treatment; Note: Oral, implantable, or injectable hormone
contraceptives are not considered effective for this study

- SUB-PROTOCOL AIM A: Any of the following treatments:

- Chemotherapy within 4 weeks before treatment with nab-rapamycin

- Hormonal therapy within 4 weeks before treatment with nab-rapamycin (with the
exception of leuprolide, degarelix, or goserelin)

- Immunotherapy within 4 weeks before treatment with nab-rapamycin

- Radiotherapy within 4 weeks before treatment with nab-rapamycin

- Treatment with nitrosoureas, mitomycin, or extensive radiotherapy within 6 weeks
before treatment with nab-rapamycin

- Immunosuppressive agents within 3 weeks before treatment with nab-rapamycin
(except corticosteroids used as antiemetics)

- Use of prior mTOR pathway inhibitor therapy

- SUB-PROTOCOL AIM A: Patients with a history of interstitial lung disease and/or
pneumonia

- SUB-PROTOCOL AIM A: Receiving any concomitant antitumor therapy or inhibitors of
cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)

- SUB-PROTOCOL AIM A: History of allergic reactions attributed to compounds of similar
chemical or biologic composition including macrolide (e.g. azithromycin,
clarithromycin, dirithromycin, and erythromycin) and ketolide antibiotics

- SUB-PROTOCOL AIM A: Major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic) =< 4 weeks prior to registration or failure to recover from side effects
of such surgery; exceptions: port placements, nephrectomy, tumor biopsies, and minor
surgeries

- SUB-PROTOCOL AIM A: Concurrent use of any other approved or investigational anticancer
agents which would be considered as a treatment for the primary neoplasm

- SUB-PROTOCOL AIM A: Patients with a history of alcoholism, drug addiction or psychotic
disorders

- SUB-PROTOCOL AIM A: Uncontrolled diabetes mellitus as defined by hemoglobin A1C
(HbA1c) > 8% despite adequate therapy; unstable coronary artery disease or myocardial
infarction during preceding 6 months; or hypertension uncontrolled by medication

- SUB-PROTOCOL AIM A: Patients who required therapeutic doses of anticoagulants