Phase I Trial of IV Fenretinide (4-HPR) Plus IV Safingol for Patients With Relapsed Malignancies

Inclusion Criteria:

Inclusion Criteria - Solid Tumor

1. Patients must have histologically or cytologically confirmed malignancy that is
metastatic or unresectable and for which standard curative or palliative measures do
not exist or are no longer effective.

2. All patients must have measurable disease documented by CT, MRI, or non-measurable
disease documented by Physical Exam within 28 days prior to registration.

3. Age >18 years.

4. ECOG performance status of 0 - 2 (Karnofsky > 60%).

5. Life expectancy of greater than 3 months.

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

- absolute neutrophil count ≥ 1,500/μL

- platelets ≥ 100,000/μL

- total bilirubin ≤ 1.5 x institutional upper limit of normal (IULN)

- AST (SGOT) ≤ 2.5 x institutional upper limit of normal (IULN) ≤ 5 x IULN for
patients with liver metastases

- ALT (SGPT) ≤ 2.5 x institutional upper limit of normal (ULN) ≤ 5 x IULN for
patients with liver metastases − creatinine within institutional normal limits
(WNL) OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine
levels above institutional normal

7. Effects of fenretinide and safingol on the developing human fetus are unknown. For
this reason, women of child-bearing potential and men 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. For women of child-bearing
potential, a negative serum pregnancy test is required within 72 hours prior to
receiving study drug each cycle. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

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

9. Patients who have received prior treatment with oral or intravenous fenretinide as a
single agent are eligible, provided they did not experience severe toxicity related to
fenretinide.

Inclusion Criteria - Non-Hodgkin's Lymphoma

1. Patients must have histologically or cytologically confirmed non-Hodgkin's lymphoma
for which standard therapies do not exist or are no longer effective. To be eligible
for this study, lymphoma patients must have no marrow involvement as documented by
routine marrow aspiration and biopsy performed within 30 days of study entry.

2. All patients must have measurable disease documented by CT, MRI, or non-measurable
disease documented by Physical Exam within 28 days prior to registration.

3. Age 18 years or greater.

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

- Absolute neutrophil count (ANC) ≥ 1500, platelets ≥ 100,000, unless due to direct
bone marrow involvement of disease.

- Hemoglobin ≥ 8.0 gm/dL; transfusion permitted to achieve this level

- Serum creatinine ≤ 1.5 x the upper limits of institutional normal (IULN)

- Total bilirubin ≤ 1.5 x the IULN

- AST/ALT ≤ 2.5 x the IULN

- Or ≤ 5 x IULN for patients with liver metastases

5. ECOG performance status of 0 - 2 and estimated survival of at least 3 months.

6. Patients must be able to understand and agree to sign an IRB-approved informed consent
form.

7. The effects of fenretinide and safingol on the developing human fetus are unknown. For
this reason,women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control) prior to study entry, for
the duration of study, and for two months after study participation. For women of
child-bearing potential, a negative serum pregnancy test is required within 72hours
prior to receiving study drug each cycle. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.

8. Patients who have received prior treatment with oral or intravenous fenretinide as a
single agent are eligible, provided they did not experience severe toxicity related to
fenretinide.

Exclusion Criteria:

1. Radiation therapy, chemotherapy, and other investigational agents within 3weeks (6
weeks for nitrosourea or mitomycin C) prior to starting fenretinide + safingol.
Patients must have recovered from toxicities of prior therapy.

2. Concurrent administration of any other investigational agents

3. Uncontrolled intercurrent illnesses including, but not limited to, ongoing or active
systemic infection, symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, coagulation disorders; other major medical illnesses of the
cardiovascular or respiratory systems or psychiatric illness/social situations that
would limit compliance with study requirements.

4. Pregnant women are excluded from this study because the effects of fenretinide and
safingol on the developing human fetus are unknown. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with fenretinide and safingol, breastfeeding must be discontinued.

5. Major surgery in the last three weeks due to unknown effects of fenretinide and
safingol on wound healing.

6. Patients with previously untreated brain metastases (including parenchymal, meningeal
or dural-based CNS lesions) are excluded. However, patients with previously treated
(surgery, radiation or both), clinically inactive brain metastases, who have not
received corticosteroid therapy within three weeks of starting protocol therapy, are
eligible.

7. Known allergy to egg products or soy bean oil.

8. Patients known to be HIV-positive receiving anti-retroviral therapy are excluded from
the study because of possible pharmacokinetic interactions.

9. Baseline fasting triglycerides > 2.5 institutional upper limit of normal (IULN) or
hypertriglyceridemia requiring medication. Patients requiring medication for other
dyslipidemias (i.e., elevated LDL cholesterol) are eligible.

10. Concomitant use of the following drugs (see Concomitant Medications, Section 3.3):
antioxidants; herbal or other alternative therapy medications; vitamin supplements
(especially vitamins A, C, and E) other than a standard dose multivitamin,
acetaminophen, cyclosporine A or analogue; verapamil; tamoxifen or analogue,
ketoconazole, chlorpromazine; RU486; indomethacin; or sulfinpyrazone, tetracycline,
nalidixic acid, nitrofurantoin, phenytoin, sulfonamides, lithium, ceftriaxone, and
amiodarone.

If the patients discontinue usage of the above drugs, they can be eligible for
enrollment into the study after a washout period of four half-lives.

11. Poorly-controlled diabetes mellitus, as defined as fasting serum glucose concentration
over 200 mg/dl or a hemoglobin A1C over 7.5%.

12. Patients with an identified familial hyperlipidemia disorder.

13. Known history of allergic reactions attributed to compounds of similar chemical or
biologic composition to fenretinide, such as 13-cis-retinoic acid, retinol, or
all-trans-retinoic acid.

14. Patients with esophageal cancer with unresected or recurrent primary tumors in the
esophagus are only permitted after discussion of patient with Study Chair due to
concern of tumor necrosis and esophageal perforation.

15. Baseline (pre-treatment) serum troponin T (TnT) ≥ 0.03 ng/mL. Troponin T levels may be
rechecked and therapy given if levels decrease to < 0.03 ng/mL.

16. Baseline (pre-treatment) EKG with any of the following changes consistent with cardiac
ischemia:

- significant ST depression (ST depression of ≥2 mm, measured from isoelectric line
to the ST segment at a point 60 msec from the end of the QRS complex)

- significant ST elevation (> 1mm in limb lead or 2 mm in precordial lead measured
at a point 0.04 sec (1 mm) after the J-point [the end of the QRS complex] and
compared to baseline [line drawn from P start to T end])