Trial Information

Phase II Dose of Escalation Design to Investigate the Therapeutic Role of RNA Fragments in the Protection of Platelet Production During Chemotherapy

Myelosuppressive chemotherapy has the potential to produce life threatening neutropenia,
anemia, and thrombocytopenia. All of these conditions compromise therapeutic dosing which
impacts survival as well as quality of life. The introduction of recombinant growth factors
has enabled oncologists to minimize or prevent the development of treatment-induced anemia
and neutropenia, but the management of chemotherapy-induced thrombocytopenia (CIT) remains a
major challenge. American Society of Clinical Oncology (ASCO) guidelines recommend dose
reduction in chemotherapy following onset of thrombocytopenia despite data showing full
dose, on time, chemotherapy leads to reduced tumor burden and better overall survival [1-3].
Patients with CIT experience potentially life threatening complications, delay in
treatment, poorer outcomes, and consume inordinate amounts of health care resources for
supportive care [4]. Development of an agent that ameliorates CIT would represent a major
breakthrough in cancer treatment.

Platelets are anuclear cell particles that are released into the bloodstream by
megakaryocytes located in the bone marrow. The differentiation of megakaryocytes is
regulated by an intricate interaction of specific cytokines and growth factors [5]. Bone
marrow stromal elements are also critical to the differentiation and release of platelets.
Cancer chemotherapy often depletes the stem and progenitor cells involved in platelet
proliferation, which leads to a diminution of platelets and temporary interruption of
platelet production lasting until stromal elements and megakaryocytes regenerate.

There are several experimental agents targeted to prevent thrombocytopenia. These
investigational agents are cytokines involved in the differentiation and production of
platelets [6]. Currently, the only agent commercially available for prevention of
thrombocytopenia is Neumega, a derivative of IL-11. Data on Neumega (Oprelekin) indicates a
shorter duration of chemotherapy-induced thrombocytopenia, but the toxicity profile has
prevented its widespread introduction into the clinical setting. Overall, the absence of
agents that minimize or reverse CIT continues to severely limit many patients' ability to
complete the full schedule of chemotherapy at the doses originally prescribed by treating
oncologists [1].

This study is a dose escalation trial investigating the anti-thrombocytopenic benefits and
safety of single stranded RNA fragments. The short chain RNA fragments are obtained by
controlled degradation of prokaryotic RNA with ribonuclease. Beljanski showed that these
RNA fragments act as primers for DNA synthesis in vitro and found that variations in the
method of degradation yielded different preparations that prime deoxyribonucleic acid (DNA)
synthesis with distinct tissue specificity. The RNA fragments used in this study, when
administered orally, localize in the bone marrow where they appear to prime DNA replication
in stem cells resulting in proliferation of white blood cells and platelets. Beljanski et
al. reported that these specific RNA fragments were effective in restoring normal levels of
circulating platelets following drug induced thrombocytopenia [7;8]. Demonstrating the
utility of these specific RNA fragments for prevention and treatment of thrombocytopenia
among cancer patients undergoing chemotherapy is especially attractive given the absence of
the side effects associated with growth factors and hormones.

This trial investigated the efficacy of two RNA preparations—extracted, purified and
fragmented according Beljanski's procedure—to ameliorate CIT: one derived from E. coli and
the second from yeast (a eukaryote). RNA molecules are present in any diet and can be
considered conditional essential nutrients under conditions of physiological stress [9].
Purified RNA prepared by various methods can be found in nutritional products for
hospitalized patients and infant formula [9-11]. This clinical trial evaluated the biologic
effects of various doses of these specially prepared 'primer' RNA fragments on platelet
numbers in cancer patients who have already developed thrombocytopenia while undergoing
chemotherapy.