This phase I trial is studying the side effects and best dose of giving ridaforolimus and vorinostat together in treating patients with advanced solid tumors or lymphoma. Giving ridaforolimus in combination with vorinostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine which dose combinations of Ridaforolimus and Vorinostat are safe and tolerable.

II. To define the maximum tolerated dose. III. To characterize dose limiting toxicities.

SECONDARY OBJECTIVES:

I. To describe the activity of this combination amongst all enrolled patients in terms of response rate, progression free survival and overall survival.

II. To describe the activity of this combination in the subset of patients with RCC in terms of response rate, progression free survival and overall survival.

III. To describe the pharmacodynamic effects of these agents in combination.

OUTLINE: This is a dose escalation study.

Patients receive ridaforolimus orally (PO) once daily on days 1-5 and vorinostat PO twice daily on days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every three months for up to 3 years.

Inclusion Criteria:

• Histological or cytological confirmation of a solid, malignant tumor or lymphoma that is refractory to standard therapies or for which no standard therapies exist
• Patients must have received at least one prior systemic therapy
• Measureable disease by RECIST v 1.1
• ECOG PS 0 or 1
• ANC >= 1500/uL
• Hgb >= 9 g/dL
• Platelets >= 100,000/uL
• AST/SGOT and ALT/SGPT =< 2.5 x upper limit of normal (ULN) or =< 5.0 x ULN in patients with liver metastases
• Total Bilirubin =< 1.5 times ULN
• Creatinine =< 2.0 mg/dL or Creatinine Clearance (calculated or 24 hour urine) >= 50 ml/min
• Female patients of childbearing potential must have a negative serum or urine pregnancy test =< 21 days of study enrollment and agree to use an effective method of contraception for the duration of the study
• Ability to understand and willingness to sign written informed consent

Exclusion Criteria:

• Prior anti-cancer treatment with either an mTOR inhibitor (i.e. temsirolimus, everolimus), or an HDAC inhibitor (i.e. Vorinostat)
• Patients who have received bevacizumab =< 6 weeks prior to day 1 of study treatment; patients who have received other chemotherapy, immunotherapy, or radiotherapy =< 3 weeks prior to day 1 of study treatment or those who have not recovered from acute adverse events due to agents administered >= 3 weeks earlier; for patients receiving targeted therapy, treatment must be discontinued at least five half-lives prior to initiation of day 1 of study treatment
• Patients who have taken valproic acid =< 2 weeks of study enrollment; valproic acid is another HDAC inhibitor
• Patients who are pregnant, plan to become pregnant, or are breastfeeding
• History of gastrointestinal bleeding within1 month of enrollment
• Serum cholesterol >= 350 mg/dL or serum triglycerides >= 400 mg/d
• Poorly controlled Type 1 or 2 diabetes, defined as hemoglobin A1C greater than 8% or a fasting glucose of > 160 mg/dL
• Active infection requiring antibiotics
• Anaphylactic reaction to macrolide antibiotics, Tween 80 (polysorbate 80)
• Patients who are not adequately recovered from a prior surgical procedure or major surgical procedure within 2 weeks prior to the first dose of study drug
• Myocardial infarction of unstable angina within 3 months of study entry
• NY Heart Association class III or IV congestive heart failure
• Known active parenchymal brain metastases; patients who have had brain metastases resected, or have received radiation therapy ending > 4 weeks prior to study entry are eligible if they meet all of the following criteria: 1) residual neurologic symptoms < grade 1, 2) no steroid requirement, 3) a follow-up MRI shows regression or stability of lesions after treatment, with no new lesions appearing
• Unable to swallow whole pills
• A requirement for one of the prohibited medications; if patient is currently taking one of these medications, they may be eligible so long as they discontinue the prohibited medication prior to starting study treatment and remain off for the duration they are taking study treatment
• Known diagnosis of HIV
• Concurrent malignancies are excluded with the following exceptions: basal cell skin cancer is allowed; cervical carcinoma in situ is allowed; any malignancy that does not require active treatment, and from which the patient has been disease free for >= 3 years is allowed

162 weeks