- Histologically or cytologically proven diagnosis of breast cancer with evidence of
metastatic or locally advanced disease, not amenable to resection or radiation therapy
with curative intent.
- Documentation of ER-positive and/or PR-positive tumor (≥1% positive stained cells)
based on most recent tumor biopsy (discuss with the Principle Investigator if results
in different biopsies are discordant in terms of hormone receptor positivity)
utilizing an assay consistent with local standards.
- Documented HER2-negative tumor based on local testing on most recent tumor biopsy:
HER2-negative tumor is determined as immunohistochemistry score 0/1+ or negative by in
situ hybridization (FISH/CISH/SISH) defined by current ASCO/CAP (American Society of
Clinical Oncology/College of American Pathologists) guidelines. Patients with
equivocal HER2 in situ hybridization results according to current ASCO/CAP guidelines
are eligible, as long as they have not received and are not scheduled to receive
- Must have progressed on at least 2 lines of endocrine therapy in either the adjuvant
or metastatic setting and progressed on a CDK4/6 inhibitor.
- Must have received no more than 4 lines of systemic therapy (for example, including
but not limited to endocrine therapy, targeted therapy, biologic therapy,
chemotherapy, or experimental therapy) for the treatment of breast cancer in the
- Premenopausal or postmenopausal female or male patients 18 years of age or older.
- Measurable disease as defined by RECIST v1.1 criteria (tumor ≥ 1 cm in longest
diameter on axial image on computed tomography (CT) or magnetic resonance imaging
(MRI) and/or lymph node(s) ≥ 1.5 cm in short axis on CT or MRI) on baseline imaging.
Bone only metastases must have associated > 10 mm soft tissue mass.
- Asymptomatic brain metastases are allowed if the lesions are not considered to need
local therapy. Previously treated brain metastases are allowed as long as they are > 4
weeks from local therapy, clinically asymptomatic, and not requiring high-dose
corticosteroids. Patients may remain on steroids for CNS disease if they are taking a
stable dose that is less than 10mg of prednisone per day, or the equivalent.
- Must be capable of understanding and complying with parameters as outlined in the
protocol and able to sign and date the informed consent, approved by the IRB, prior to
the initiation of any screening or study-specific procedures.
- Life expectancy of more than 3 months.
- ECOG performance status 0-1
- Pregnancy must be ruled out in women of childbearing potential. Serum or urine
pregnancy test must be negative within 14 days of treatment start in women of
childbearing potential and must be willing to have pregnancy test approximately every
4 weeks. Pregnancy testing does not need to be pursued in patients who are judged to
be postmenopausal before enrollment, or who have undergone bilateral oophorectomy,
total hysterectomy, or bilateral tubal ligation. Patients may be considered
postmenopausal in the case that one of the following criteria applies,
- Prior bilateral oophorectomy, OR
- Age ≥ 60 years, OR
- Age < 60 years with intact uterus and amenorrhoeic for ≥ 12 consecutive months
prior to chemotherapy and/or endocrine therapy exposure
- Willingness to utilize adequate contraception if of childbearing potential. Women of
childbearing potential must use adequate contraception for the duration of protocol
treatment and for at least 6 months after the last treatment with SM-88 used with MPS.
Adequate contraception is defined as one highly effective form (i.e., abstinence,
(fe)male sterilization) OR two effective forms (IUD [non-hormonal preferred], condom
with spermicidal foam / gel / film / cream / suppository, occlusive cap with
spermicidal foam / gel / film / cream / suppository).
- Must be able and willing to swallow pills whole and retain oral medication.
- Adequate hematologic parameters (Patients must be able to meet the following criteria
without transfusion or receipt of colony stimulating factors within 2 weeks before
- Absolute neutrophil count (ANC) ≥ 1,500/mm3; Patients must be able to meet the
criteria without receipt of colony stimulating factors within 2 weeks before
- Platelets ≥ 100,000/mm3; Patients must be able to meet the criteria without
receipt of transfusion within 2 weeks before obtaining sample
- Hemoglobin ≥ 9 g/dL; Patients must be able to meet the criteria without receipt
of transfusion within 2 weeks before obtaining sample
- Serum creatinine clearance ≥ 60 mL/min based on Cockcroft-Gault equation
- Adequate hepatic parameters:
- Aspartate aminotransferase (AST) and/or Alanine aminotransferase (ALT) ≤ 3 x ULN
(upper limit of normal)
- Total serum bilirubin ≤ 1.5 x ULN, except for patients with a documented history
of Gilbert's Syndrome who can be enrolled at PI discretion
- For patients with liver metastases, AST and ALT < 5x the institution's ULN and/or
total bilirubin ≤ 3.0x the institution's ULN are acceptable as long as there is
no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever,
- Alkaline phosphatase ≤2.5 x ULN (≤5.0 x ULN if bone metastases present)
- Resolution of all acute toxic effects of prior therapy, including radiotherapy to
grade ≤1 (except toxicities not considered a safety risk for the patient) and recovery
from surgical procedures.
- Must have discontinued all previous therapies for cancer (including endocrine therapy,
CDK4/6 inhibitor therapy, cytotoxic chemotherapy, targeted therapy [including, but not
limited to, everolimus], radiotherapy, immunotherapy, and investigational therapy) for
at least 14 days prior to receiving study drugs and recovered from the acute effects
of therapy (treatment-related toxicity resolved to baseline) except for residual
alopecia or peripheral neuropathy.
- Concurrent therapy with other approved or investigational cancer treatment agents,
except bisphosphonates and RANKL inhibitors.
- Bone-only metastases without soft tissue masses measuring > 10 mm.
- Inability to comply with study requirements.
- Diagnosis of other invasive cancer except for adequately treated cervix cancer, or
more than 5 years since other diagnosis of invasive cancer (including invasive
squamous cell cancers due to contraindication for methoxsalen use) without current
evidence of disease.
- Pregnant women or women of childbearing potential without a negative pregnancy test
(serum or urine) within 14 days prior to starting study treatment.
- Breastfeeding must be discontinued prior to study entry.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled
nausea/vomiting, chronic diarrhea, malabsorption syndrome, intestinal obstruction, or
small bowel resection)
- Patients with clinically significant liver disease, including active viral or other
known active hepatitis, current alcohol abuse, or cirrhosis.
- Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg])
or active hepatitis C (defined as positive test for hepatitis C viral load by
polymerase chain reaction [PCR]).
- Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
(defined as having a negative HBsAg test and a positive antibody to hepatitis B
core antigen [anti-HBc] antibody test) are eligible.
- Patients with positive hepatitis C antibody AND negative quantitative hepatitis C
by PCR AND no clinical/laboratory evidence of cirrhosis are eligible. Patients
who have completed curative therapy for HCV are eligible if they meet all other
parameters for enrollment.
- Uncontrolled HIV infection defined as any of the following 3 criteria: CD4 counts ≤
350 cells/μL; serum HIV viral load ≥ 400 copies/mL; on a antiretroviral regimen for <
4 weeks prior to treatment with study drugs if anti-retroviral therapy is deemed
necessary or appropriate by the investigator.
- Previous enrollment in this study or any other study investigating SM-88.
- History of any known drug allergies to any study medication.
- Clinically significant and uncontrolled major medical condition(s) including, but not
limited to uncontrolled nausea/vomiting/diarrhea; active, uncontrolled infection;
symptomatic congestive heart failure (New York Heart Association [NYHA] class ≥ II);
unstable angina pectoris; cardiac arrhythmia requiring hospitalization in the past 3
months; stroke or MI in the past 6 months.
- Psychiatric illness or social situation that would limit compliance with study
- Active uncontrolled or symptomatic brain metastases. Previously treated and clinically
stable brain metastases, as per Investigator's judgement, are permitted.
- Patients with a seizure disorder that is not well controlled or who have required a
change in seizure medications within 60 days of enrollment to the trial.
- Patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or
other hydantoins; or a history of prior acute hepatotoxicity attributable to
- Patients treated, or anticipated to be treated, with delavirdine (due to potential for
loss of virologic response and possible resistance to delavirdine or to the class of
non-nucleoside reverse transcriptase inhibitors caused by phenytoin).
- Patients exhibiting idiosyncratic reactions to psoralen compounds.
- Patients with a history of the light sensitive diseases for which methoxsalen would be
contraindicated. Diseases associated with photosensitivity include lupus
erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate
porphyria, xeroderma pigmentosum, and albinism.
- Patients with cutaneous melanoma or invasive squamous cell carcinomas or a history
thereof, except for those with stage 1A melanoma or in complete remission for ≥5 years
(due to contraindication for use of methoxsalen).
- Patients with a hypersensitivity to sirolimus. Sirolimus does cause immune suppression
at the prescribed doses and physicians should note the drugs black box warning to
exclude any patient they believe the other exclusion criteria does not reflect.
- Patients with prior allogenic bone marrow transplant or solid organ transplant organ
transplant or being treated, or anticipated to be treated, with cyclosporine (because
long-term administration of the combination of cyclosporine and sirolimus is
associated with deterioration of renal function).
- Patients treated, or anticipated to be treated, with a calcineurin inhibitor (because
concomitant use of sirolimus and a calcineurin inhibitor increases the risk of
calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic
purpura/thrombotic microangiopathy [HUS/TTP/TMA]).
- Clinically significant cataracts or aphakia (absence of lens over the eye, typically
from cataract surgery, trauma, or congenital anomaly).
- Current use of known strong inhibitors or inducers of CYP3A4, CYP2C9 or CYP2C19 within
14 days of initiation of study drug. When possible these medications and grapefruit
juice should be avoided for the duration of the study treatment and alternate
therapies are preferred.