Onalespib in Treating Patients With Relapsed or Refractory Anaplastic Large Cell Lymphoma, Mantle Cell Lymphoma, or Diffuse Large B-Cell Lymphoma

PRIMARY OBJECTIVES:

I. Overall response rate (ORR) to single agent AT13387 (onalespib) as measured by the
proportion of partial and complete responses (PR + CR) in patients with relapsed/refractory
ALK positive (+) anaplastic large cell lymphoma (ALCL), mantle cell lymphoma (MCL), and BCL6+
diffuse large B cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. Progression free survival (PFS) and overall survival (OS), as well as duration of response
(DOR) of single agent AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

II. Safety and tolerability of single agent AT13387 (onalespib) in patients with ALK+ ALCL,
MCL, and BCL6+ DLBCL.

TERTIARY OBJECTIVES:

I. Measurement of on-target activity of AT13387 (onalespib) in ALK+ ALCL, MCL, and BCL6+
DLBCL through immunoblotting and immunohistochemistry of pre-treatment, on-treatment, and
time of progression tumor biopsies for HSP90 clients.

II. Determination of genetic and transcriptional markers for response and resistance to
AT13387 (onalespib) in patients with ALK+ ALCL, MCL, and BCL6+ DLBCL.

OUTLINE:

Patients receive onalespib intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 1
year.

Inclusion Criteria:

- Patients must have histologically confirmed, relapsed/refractory ALK+ ALCL (with ALK
positivity defined by immunohistochemistry and/or fluorescence in situ hybridization
[FISH]/cytogenetics from any prior biopsy), MCL, or BCL6+ DLBCL (with BCL6 positivity
defined by immunohistochemistry from any prior biopsy) and meet the following
criteria:

- Patients must have measurable disease that has not been previously irradiated, defined
as at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions and short axis for nodal
lesions) as >= 20 mm (>= 2 cm) with conventional imaging or >= 10 mm with spiral
computed tomography (CT) scan; if the patient has been previously irradiated, there
must be evidence of progression since the radiation

- Please note, this trial includes mandatory tumor biopsies pre-treatment, during
cycle 1 and at the time of disease progression of accessible tumor; having
accessible tumor for biopsy is not required for eligibility; we expect that at
least 80% of patients will have accessible tumor for these biopsies, however

- ALK+ ALCL: patients must have disease that has relapsed and or is refractory to prior
therapy, which must have included a multiagent chemotherapy regimen including an
anthracycline, if not contraindicated, and prior brentuximab; prior crizotinib or
other ALK inhibitor therapy, while recommended, is not mandatory; patients must have
relapsed following or be ineligible for, or refuse, autologous stem cell transplant

- MCL: patients must have disease that has relapsed and or is refractory to prior
therapy, which must have included a multiagent chemotherapy regimen and prior
ibrutinib or other BTK inhibitor therapy; patients must have relapsed following or be
ineligible for, or refuse, autologous stem cell transplant

- BCL6+ DLBCL: patients must have disease that has relapsed and or is refractory to
prior therapy, which must have included an anthracycline, if not contraindicated;
patients must have relapsed following or be ineligible for, or refuse, autologous stem
cell transplant

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 75,000/mcL, unless due to marrow involvement by lymphoma in which case a
platelet count of >= 30,000/mcL will be used

- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome
or hemolysis, in which case =< 3.0 x ULN is allowed

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 x institutional upper limit of normal

- Creatinine =< 1.5 x ULN or a creatinine clearance >= 50 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Potassium above the institutional lower limit of normal (supplementation to meet this
is allowed)

- Magnesium above the institutional lower limit of normal (supplementation to meet this
is allowed)

- Human immunodeficiency virus (HIV)+ patients are eligible for the trial provided they
meet the other study criteria in addition to the following:

- CD4+ T-cells >= 250/mm^3

- HIV sensitive to antiretroviral therapy

- Zidovudine not allowed

- Long term survival anticipated on the basis of HIV alone were it not for the
lymphoma

- No concurrent acquired immunodeficiency syndrome (AIDS)-defining illness other
than the lymphoma

- 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, for
the duration of study participation, and for 4 months after the completion of AT13387
(onalespib) administration; 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; men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of AT13387 (onalespib) administration

- Patients must be willing to not take St. John wort or grapefruit juice while
participating in this trial and should avoid drugs that are strong inducers of P-gp,
and to switch to alternative drugs when available

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

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier;
steroids for symptom palliation are allowed, but must be either discontinued or on
stable doses at the time of initiation of protocol therapy

- Patients who are receiving any other investigational agents; all investigational
agents other than ibrutinib must have been discontinued at least 4 weeks prior to
beginning treatment; prior ibrutinib therapy must have been discontinued at least 2
weeks prior to beginning therapy

- Patients with known leptomeningeal or brain metastases should be excluded from this
clinical trial; imaging or spinal fluid analysis to exclude central nervous system
(CNS) involvement is not required, unless there is clinical suspicion by the treating
investigator

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AT13387 (onalespib)

- 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

- There will be no exclusion of patients with known visual impairment or symptoms,
including by not limited to peripheral flashes (photopsia), blurred or double
vision, floaters, color distortion and dimness, difficulties with light/dark
accommodation, tunnel vision or other field defects, halos, apparent movement of
stationary objects, and complex disturbances; patients will have a baseline
ophthalmologic exam to serve as a point of comparison and further exams as needed
should visual symptoms develop; no pretreatment eye exam findings or ocular
symptoms have been associated with an increased risk of ocular toxicity seen with
AT13387

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with AT13387 (onalespib)

- Patients, who have had a major surgery or significant traumatic injury within 4 weeks
of start of study drug, patients who have not recovered from the side effects of any
major surgery (defined as requiring general anesthesia) or patients that may require
major surgery during the course of the study

- Prior history of another malignancy (except for non-melanoma skin cancer or in situ
cervical or breast cancer) unless disease free for at least three years; patients with
prostate cancer are allowed if prostate specific antigen (PSA) is less than 1

- Patients should not receive immunization with attenuated live vaccine within one week
of study entry or during study period

- History of noncompliance to medical regimens

- Consistent corrected QT (QTc) > 450 msec for men and > 470 msec for women by
Fridericia formula, on 3 separate electrocardiograms (ECGs)

- Left ventricular ejection fraction (LVEF) < 50%, regardless of whether there are
symptoms of heart failure