A Phase I Study of the mTOR Inhibitor Rapamycin (Rapamune, Sirolimus) in Combination With Abraxane (Paclitaxel Protein-Bound Particles) in Advanced Solid Cancers
- Patients must have histologically-confirmed advanced solid tumors.
- For patients with metastatic breast cancer, there will be no restriction on prior
therapy. For patients with other advanced solid tumors, they must be refractory to
standard therapy or for which no curative standard therapy exists, to be considered.
Metastatic disease, if present, should not be progressing so as to require palliative
treatment within 4 weeks of enrollment based on clinical assessment by the
- Development of new lesions or an increase in preexisting lesions on bone
scintigraphy, CT, MRI or by physical examination. Patients in whom the sole
criterion for progression is an increase in a biochemical marker, e.g.,
carcinoembryonic antigen (CEA), or an increase in symptoms, are not eligible.
- No radiotherapy, treatment with cytotoxic agents, or treatment with biologic agents
within the 4 weeks prior to beginning treatment on this study (6 weeks for mitomycin
or nitrosoureas). At least 2 weeks must have elapsed from any prior surgery or
hormonal therapy. Patients must have fully recovered from the acute toxicities of any
prior treatment with cytotoxic drugs, radiotherapy or other anti-cancer modalities
(returned to baseline status as noted before most recent treatment). Patients with
persisting, stable chronic toxicities from prior treatment ≤ grade 1 are eligible.
- Age ≥18 years.
- ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
- Life expectancy of greater than 3 months.
- Patients must have normal organ and marrow function as defined below:
Hemoglobin ≥ 9 g/dL leukocytes ≥3,000/mcL absolute neutrophil count ≥1,500/mcL platelets
≥100,000/mcL total bilirubin within normal institutional limits AST(SGOT)/ALT(SGPT)2.5 X
institutional upper limit of normal creatinine within 1.5 x ULN OR creatinine clearance
≥50 mL/min/1.73 m² for patients with creatinine levels ≥1.5 ULN.
- Women of child-bearing potential must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation and must have a negative serum or urine pregnancy
test within 1 week prior to beginning treatment on this trial. Pregnant and nursing
patients are excluded because the effects of the combination of Abraxane and
Rapamycin on a fetus or nursing child are unknown. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately. Sexually active men must also use appropriate
contraception method and should not father a child while receiving therapy during
- Ability to understand and the willingness to sign a written informed consent
- Fasting serum cholesterol <350 mg/d L and triglycerides < 400 mg/ d L.
- Biopsy is required but patients or physicians may opt out of this part of the trial
if sufficient justification is provided. Justification must be provided to the PI in
writing indicating excessive physical risk or psychological trauma if biopsy is taken
- Patients must be 4 weeks from chemotherapy or radiotherapy and have recovered from
any adverse events
- Patients may not be receiving any other investigational agents.
- Patients with known active brain metastases. Patients must have completed definitive
treatment for brain metastases, at least 4 weeks prior to first dose on this study,
and off steroids for at least 2 weeks, with stable or regressing CNS lesions by MRI
or CT scan, and no evidence of new lesions.
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to agents used in study.
- Peripheral neuropathy ≥ Grade 2
- 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
- Pregnant women are excluded from this study because the investigational agents may
have the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with these agents, breastfeeding should be discontinued if
the mother is treated.
- HIV-positive patients are ineligible because these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy and the potential
pharmacokinetic interaction between antiretroviral therapy and the investigational
- All herbal and alternative medications should be discontinued while on study, these
include but not limited to: Hydrastis canadensis (goldenseal), Uncaria tomentosa
(cat's claw) Echinacea angustifolia
- Use of any of these medications within 1 week, prior to the first dose of treatment:
cyclosporine, diltiazem, ketoconazole, rifampin, fluconazole, delavirdine,
nicardipine, pioglitazone and sulfonamides, erythromycin, clarithromycin,
itraconazole, metoclopramide, nevirapine, Phenobarbital, phenytoin, indinavir
fosamprenavir, ritonavir, efavirenz, nefazadone, and St. John's wort.
- Consumption of grapefruit juice is prohibited during the study.
- Requirement for treatment with warfarin (Coumadin), immunosuppressive agents or
- Prior therapy with rapamycin, rapamycin analogs or experimental agents targeting mTOR
- Prior Abraxane therapy
- Active infection or treatment for systemic infections within 14 days of enrollment.