Romidepsin Versus Combination of Romidepsin Plus Pralatrexate in PTCL

Over the past 8 years, 3 new classes of drugs have been approved for the group of diseases
recognized as peripheral T-cell lymphoma (PTCL). The novel anti-folate pralatrexate was the
first drug approved for patients with relapsed or refractory PTCL in 2009. Four histone
deacetylase (HDAC) inhibitors have been approved including vorinostat, romidepsin,
belinostat, and chidamide (approved in China). The antibody drug conjugate Brentuximab
vedotin was approved in one subtype of PTCL, anaplastic large T-cell lymphoma. The HDAC
inhibitors and pralatrexate exhibit near lineage-specific activity with limited-to-no
activity in B-cell lymphomas. As single agents in the relapsed setting romidepsin and
pralatrexate exhibit response rates of 25-38% and 29-54% respectively across published phase
I and II studies. While these studies are not identical in their patient composition, they
included patients who are heavily pre-treated from a diversity of PTCL subtypes. A recent
case match control analysis has demonstrated that patients treated with pralatrexate on
PROPEL achieve a statistically significant survival advantage when compared to a matched
historical population. In addition, sub-analysis of patients treated on PROPEL revealed that
response and clinical benefit metrics (ORR, CR, duration of response (DOR) and progression
free survival (PFS)) with pralatrexate improved significantly as the therapy moved up earlier
in their treatment course. Patients achieving a response to romidepsin also exhibited a
prolonged DOR of 28 months, with the median DOR not being reached in patients achieving
complete response (CR).

The curative treatment of PTCL is not likely to be accomplished by the use of any single
agent therapies. Clinically it makes sense to identify rational combinations of active agents
in an attempt to identify disease specific active combinations. In preclinical models of
T-cell lymphoma, in vitro cytotoxicity assays have clearly established a synergistic
interaction between pralatrexate and several HDACI, including romidepsin. In addition,
pralatrexate and romidepsin have differing mechanisms of actions and different toxicity
profiles which lends to the probability that the combination of these agents will be combined
safely with likely improved efficacy. Despite this rationale, the identification of a
biological rationale will provide important insights into the optimal strategies for combing
these different classes of drugs. It will also provide opportunities to develop biomarkers of
response.

Peripheral T-cell lymphoma (PTCL) is extremely rare especially in the United States and
Europe and is associated with considerable heterogeneity. Of the lymphomas, T-cell lymphomas
make up a larger fraction in Asia and Latin America likely owing to genetic predisposition
and early exposure to viral infections such as human T-lymphotropic virus type -1 (HTLV-1)
and Epstein barr virus (EBV). Although there are differences between subtypes, in general
patients with T-cell lymphomas have an inferior overall survival as compared to those with
their B-cell lymphoma counterparts. The median overall survival of patients with T-cell
lymphoma is only 1 to 3 years. There is presently no consensus on the best front-line therapy
for these patients, though most recognize cyclophosphamide- doxorubicin hydrochloride
(Adriamycin)-vincristine (Oncovin)-prednisolone (CHOP) or CHOP-based treatment as the
standard despite the poor results. While clinical trials have been important in identifying
novel agents active in relapsed disease, accrual to trials is often difficult given the
rarity of the disease. Incorporation of novel agents into the front-line setting has not yet
been realized.

Modest attempts to improve responses and duration of response have been made by intensifying
front-line chemotherapy with the addition of etoposide and by consolidating response with
autologous stem cell transplantation in the first remission, though these maneuvers have
likely not significantly impacted the natural history of the disease.

Over the past several years, the investigators have adopted a strategy of trying to develop
novel T-cell lymphoma active combinations, based on drug: drug synergy experiments in the
preclinical setting. For example, the investigators have established biological preclinical
and clinical evidence for the following doublets: (1) pralatrexate plus romidepsin (2)
hypomethylating agents and HDAC inhibitors (3) pralatrexate plus gemcitabine.(4) pralatrexate
plus bortezomib and (5) alisertib plus romidepsin. Each of these combinations leveraged a
strong rationale for the companion agent used in combination with the HDAC inhibitor and or
pralatrexate, leading to a clinical study in most cases.

Results from the phase I portion of the study demonstrate that the combination is safe and
produces clinically meaningful responses across a diversity of PTCL subtypes in patients who
are heavily treated. Twenty-nine patients were enrolled and were evaluable for toxicity.
There were 3 dose-limiting toxicities (DLTs) in cohort 4 (pralatrexate 20mg/m2 & romidepsin
12mg/m2given weekly x 2 Q21D) consisting of 2 Grade 3 oral mucositis and 1 Grade 4 sepsis.
The every other week (QOW Q28D) schedule had no DLTs at equivalent and higher doses. The
grade 3/4 toxicities reported in >5% of patients included: neutropenia (28%),
thrombocytopenia (28%), anemia (29%), oral mucositis (14%), hyponatremia (7%), pneumonia (7%)
and sepsis (7%). Twenty-three patients were evaluable for response. The overall response rate
(ORR) in the total, non-PTCL and PTCL populations was 57%; 33% (no CR) and 71% (40% CR)
respectively. Given these are two approved agents for relapsed PTCL, there is a clear
regulatory strategy following the completion of this study.

Inclusion Criteria:

- Patients must have histologically confirmed relapsed or refractory aggressive
peripheral T-cell lymphoma as defined by 2016 World Health Organization (WHO) criteria
(excluding nasal natural killer t-cell (NK-T) and blastic natural killer (NK))

- Patients are required to have no more than 5 lines of prior therapy (with
cytoreductive therapy followed by autologous stem cell transplant counting as one line
of therapy. Patients are eligible if they have relapsed after prior autologous or
allogeneic stem cell transplant

- Measurable Disease

- Age >18 years

- Eastern Cooperative Oncology Group (ECOG) performance status <2

- Patients must have adequate organ and marrow function

- Adequate contraception

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

Exclusion Criteria:

- Prior Therapy

- Prior exposure to pralatrexate or a histone deacetylase inhibitor (romidepsin,
chidamide, belinostat, or vonrinostat)

- Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or
those who have not recovered from adverse events due to agents administered more than
2 weeks earlier.

- Systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day
prednisone prior to the start of the study drugs.

- No other concurrent investigational agents are allowed.

- Central nervous system metastases, including lymphomatous meningitis

- Uncontrolled intercurrent illness

- Pregnant women

- Nursing women

- Current malignancy or history of a prior malignancy

- Patient known to be Human Immunodeficiency Virus (HIV)-positive

- Active Hepatitis A, Hepatitis B, or Hepatitis C infection