Summaries of recent solicitations for letters of intent for
investigational agents available through CTEP are listed below. For
additional information, contact the designated NCI Senior Investigator.
Contact information can be found at:
<http://ctep.cancer.gov/forms/CTEP_staff.xls>

**GX15-070 ( obatoclax mesylate)**

**[Solicitation for 1. Phase 1 Combination Trials of GX15-070 (NSC \#
729280) with Standard Agents Suitable for Patients with Chronic
Lymphocytic Leukemia, Non-Hodgkin\'s Lymphoma, Multiple Myeloma, and
Small Cell Lung Carcinoma. 2. Proposals For Preclinical Studies with
GX15-070]{.smallcaps}**

**Submit Letters of Intent (LOIs) for all trials by August 9, 2006**

**CONTACT: Janet E. Dancey, M.D., <danceyj@ctep.nci.nih.gov>**

The Cancer Therapy Evaluation Program (CTEP) is soliciting proposals for
clinical trials to evaluate the anti-tumor activity of GX15-070, a novel
small molecule inhibitor of the Bcl-2 protein family. GX15-070 is also
known as obatoclax mesylate and is supplied to CTEP by GeminX
Biotechnologies, Inc. Studies suggest that GX15-070, administered
intravenously (IV), induces apoptosis by inhibiting the interaction
between pro- and anti-apoptotic proteins. Inhibition of anti-apoptotic
Bcl-2 family proteins by GX15-070 sensitizes tumor cells to the
pro-apoptotic stress signals inherent in tumor cells leading to cell
death. Phase 1 combination studies of GX15-070 in combination with
standard agents suitable for patients with chronic lymphocytic leukemia
(CLL), non-Hodgkin\'s lymphoma (NHL), small cell lung carcinoma (SCLC),
and multiple myeloma (MM), are of interest to CTEP. In addition, phase 1
combination studies with the following agents are of interest: 1)
bortezomib - to be subsequently evaluated in myeloma and mantle cell,
and 2) fludarabine, and/or fludarabine + rituximab and other
combinations relevant for second-line treatment of CLL, MM, and other
lymphoid malignancies. In addition, phase 1 combination studies relevant
to the treatment of second-line SCLC are of interest. Disease specific
phase 1/2 studies or phase 1 studies in patients with solid tumors
(including lymphoma), followed by disease specific phase 2 studies are
of interest. Randomized phase 2 studies evaluating the addition of
GX15-070 to standard treatment are preferred.

In anticipation of future CTEP solicitation for other Phase 1/2 trials,
CTEP is also soliciting proposals for pre-clinical studies with
GX15-070. The primary goal of this solicitation is to identify areas for
further clinical investigation. Please note that no additional CTEP
funds will be available to support preclinical studies. Studies of
interest include assessment of potential predictive markers of activity
and assessment of combinations of GX15-070 with direct clinical
applicability, such as in combination with cytotoxic chemotherapy,
combinations of agents that target growth factor-signaling pathways,
downstream targets within RAS-RAF-MEK , or PI3K-AKT- mTOR, agents
targeting components of different malignant processes such as
angiogenesis, and other components of the intrinsic or extrinsic
apoptotic pathways. Assessment of combinations at clinically relevant
concentrations across panels of cell lines for synergy/additivity and
scheduling effects is of particular interest. Note that cell lines need
not be limited to histologies requested in this solicitation for phase
1/2 studies.

**AZD6244 (ARRY-142886).**

**[Solicitation for:]{.smallcaps} [1. Letters of Intent for Single-Agent
Trials of AZD6244 (NSC 741078) in Patients with ]{.smallcaps}**
**[Ovarian Borderline Tumors, Papillary Thyroid, or
Hepatocellular/Biliary Carcinoma, Multiple Myeloma, and Acute Myeloid
Leukemia]{.smallcaps}**

**[2. Proposals For Preclinical Studies with AZD6244.]{.smallcaps}**

**Submit Letters of Intent (LOIs) for all trials by July 26, 2006**

**CONTACT: Janet E. Dancey, M.D., <danceyj@ctep.nci.nih.gov>**

The Cancer Therapy Evaluation Program (CTEP) is soliciting proposals for
clinical trials to evaluate the anti-tumor activity of AZD6244 (also
known as ARRY-142886). Under development by AstraZeneca, AZD6244 is an
orally administered, un-competitive inhibitor of the mitogen-activated
protein kinase kinase (MEK)-1/2. Single-agent studies in patients with
ovarian serous or mucinous borderline tumors, papillary thyroid,
hepatocellular or cholangio/biliary carcinomas, and haematological
indications including acute myeloid leukemia, and multiple myeloma
syndrome, are of particular interest.

In anticipation of future CTEP solicitation for other Phase 1/2 trials,
CTEP is also soliciting proposals for pre-clinical studies with AZD6244.
The primary goal of this solicitation is to identify areas for further
clinical investigation. Studies of interest include: 1) identification
of biomarkers that correlate with sensitivity/resistance to AZD6424 and
2) combinations of AZD6244 with direct clinical applicability. The
latter may include such as in combination with cytotoxic chemotherapy,
combinations of agents that target growth factor-RAS-RAF-MEK signaling
pathway, targets within different pathways (e.g. survival signaling
pathways, mTOR, AKT) and agents targeting components of different
malignant processes. Assessment of combinations at clinically relevant
concentrations across panels of cell lines of known RAS and RAF
mutational status for synergy/additivity and scheduling effects is of
particular interest. Note that cell lines need not be limited to
histologies requested in this solicitation for phase 2 studies.

**Pertuzumab (rhu Mab 2C4, Omnitarg)**

**Solicitation for ph ½ trial in combination with cetuximab in patients
with colorectal cancer**

**Submit Letters of Intent (LOIs) for all trials by April 26, 2006**

**CONTACT: Helen Chen, M.D., <chenh@ctep.nci.nih.gov>.**

The Cancer Therapy Evaluation Program (CTEP) is soliciting clinical
trials with **pertuzumab (rhu Mab 2C4, Omnitarg),** a humanized
monoclonal antibody that binds to the HER-2 and blocks its ability to
dimerize with other HER receptors. The current solicitation is for one
Phase 1/2 trial for the combination of pertuzumab with cetuximab in
patients with colorectal cancer (CRC). Correlative studies that aim at
exploring potential predictive markers of pertuzumab therapy should be
incorporated into the proposals.

**Reovirus Serotype 3 -- Dearing Strain (Reolysin^®^) (NSC 729968)**

**Clinical trials in melanoma and ovarian cancer**

**Submit Letters of Intent (LOIs) for all trials by February 24, 2006**

**CONTACT: James Zwiebel, M.D.,
[zwiebelj@ctep.nci.nih.gov](mailto:jz43j@nih.gov)**

Reovirus Serotype 3 -- Dearing Strain is a naturally occurring,
ubiquitous, non-enveloped human reovirus with a genome that consists of
10 segments of double-stranded RNA. While community-acquired reovirus
infection in humans is generally mild and limited to the upper
respiratory and gastrointestinal tract, reovirus has been shown to
replicate specifically in, and be cytopathic to, transformed cells
possessing an activated Ras signaling pathway. The specificity of the
reovirus for Ras-transformed cells, coupled with its relatively
nonpathogenic nature in humans, makes it an attractive anti-cancer
therapy candidate.

[]{.mark}

CTEP is soliciting for a phase 2 study of reovirus administered
systemically in patients with **melanoma**. The dose to be used in this
study will be determined from the phase 1 studies conducted by
Oncolytics Biotech, Inc. Endpoints are to be both clinical and
biological, including whether the virus will infect and replicate within
tumors.

CTEP is also soliciting for a phase 1/2 study of reovirus administered
systemically and as an intraperitoneal (IP) injection in patients with
**ovarian cancer**. The purpose of the phase 1 portion of the trial is
to determine the MTD of systemic plus IP administration. The phase 2
portion of the trial will then determine clinical activity and whether
the virus will infect and replicate within tumors.

**DASATINIB (BMS-354825) (NSC 732517)**

**Solicitation for phase 2 studies in solid tumors**

**Letters of Intent due: January 11, 2006**

**CONTACT: John J. Wright, M.D., Ph.D., <wrightj@ctep.nci.nih.gov>**

Dasatinib (BMS-354825) is a potent inhibitor of at least five selected
protein tyrosine kinases/kinase families including, SRC family kinases,
BCR-ABL, c-KIT, EPHA2 receptor, and PDGFβ receptor. Dasatinib is an
orally bioavailable BCR-ABL kinase inhibitor with a two-log increased
potency relative to imatinib and retains activity against 14 of 15
imatinib (Gleevec®)-resistant BCR-ABL mutants. Dasatinib is being
developed by CTEP as an anticancer agent in collaboration with
Bristol-Myers Squibb. CTEP is requesting Letters of Intent (LOIs) for
single-agent phase 2 trials of dasatinib for the treatment of solid
tumors in **colorectal, NSCLC, SCLC, pancreas, hepatocellular, melanoma,
glioma, squamous cell carcinoma of the head & neck, sarcoma and squamous
cell skin cancer**

**[VEGF Trap (NSC 724770)]{.underline}**

**Clinical trial in glioblastoma**

**Letters of Intent due 11/16/2005**

**CONTACT: Alice Chen, M.D., <chenali@mail.nih.gov>.**

VEGF Trap, an unique fusion protein combining the Fc portion of human
IgG~1~ with the principal extracellular ligand-binding domains of human
vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR
receptor 2 (VEGFR2), acts as a high-affinity soluble VEGF receptor and
potent angiogenesis inhibitor. VEGF Trap is being developed by CTEP as
an anticancer agent in collaboration with sanofi-aventis/Regeneron
Pharmaceuticals, Inc. CTEP is soliciting for proposals for a
single-agent Phase 2 clinical trial of VEGF Trap in recurrent
glioblastoma.

CTEP is soliciting for a Phase II clinical trial of single-agent VEGF
Trap (NSC 724770). VEGF Trap will be given (TBD) mg/kg biweekly.
Patients must have previously been treated with resection, radiation and
Temozolomide. Patients must have a PS of 0-1 with an expected survival
of greater than 3 months. Please include in your letter of intent
expected accrual and documented accrual from previous studies in a
similar patient population.

#### GW786034 (NSC #737754

#### CTEP Solicitation of Phase 1 and Phase 2 Studies

**Letters of intent due 9/30/2005**

**Contact: Dr Percy Ivy ivyp@ctep.nci.nih.gov**

CTEP is soliciting proposals to conduct phase 1 combination agent and
phase 2 single-agent clinical trials of GW786034 (NSC #737754). GW786034
is a novel, multi-targeted, small molecule inhibitor of human VEGFR-1,
-2, and -3, PDGFR- and --, and c-kit tyrosine kinases (TKs). GW786034
showed significant antitumor and antiangiogenic activity in a number of
human tumor xenograft and angiogenesis models in mice.

CTEP requests Letters of Intent (LOIs) for phase 2 single-agent studies
of GW786034 in patients with relapsed/refractory solid tumors
(specifically, breast, neuroendocrine, GIST, mesothelioma, bladder, and
thyroid). The intent of these studies is to determine if the drug is
efficacious in these diseases.

Additionally, CTEP requests LOIs for phase 1 combination agent studies
of GW786034 with other novel agents, especially those with
non-overlapping molecular target(s) and spectrum of AEs. Such
combination studies include but are not limited to GW786034 in
combination with Herceptin or a SERM for breast cancer, erlotinib or
other chemotherapies for NSCLC, hormonal agents in prostate cancer, src
inhibitors in GIST, and radiation therapy in GBM, rectal, and SCCHN.

**Sunitinib (SU11248)**

**Request for phase 2 trials**

**Letters of intent due 11/30/2005**

**Contact: Dr Percy Ivy ivyp@ctep.nci.nih.gov**

CTEP is soliciting proposals to conduct phase 2 single-agent clinical
trials of sunitinib (SU11248) (NSC #736511). Sunitinib is a novel,
multi-targeted, small molecule inhibitor of the receptor tyrosine
kinases (RTKs) involved in tumor proliferation and angiogenesis,
including vascular endothelial growth factor receptor-1 (VEGFR-1), -2,
and -3, PDGFR- and -, stem cell receptor factor (KIT), the tyrosine
kinase (TK) receptor encoded by the (rearranged during transfection)
*ret* proto-oncogene (RET), and fms-like tyrosine kinase 3 (Flt3).
Sunitinib selectively inhibits the Class 3 and Class 5 split-kinase
domain RTKs. Sunitinib is being developed by CTEP in collaboration with
Pfizer, Inc, under a Clinical Trials Agreement (CTA). Sunitinib showed
significant antitumor and antiangiogenic activity in a number of human
tumor xenograft and angiogenesis models in mice, as well as in phase 1
and 2 studies in patients with a variety of tumor types (Sakamoto,
2004). In two phase 2 trials in patients with cytokine-refractory
metastatic renal cell carcinoma (RCC), sunitinib produced objective
responses in 38% of patients (n=169), with a median time to progression
of 8.7 months (Motzer *et al*., 2005). Additionally, sunitinib showed
superiority compared to placebo for time-to-progression (TTP) and
overall survival (OS) in a phase 3 trial in patients with
imatinib-resistant gastrointestinal stromal tumors (GIST).

CTEP is soliciting for phase 2 single-agent studies of sunitinib in
patients with gynecologic cancers (ovarian, endometrial, and cervical),
pancreatic cancer, glioma, medullary and papillary thyroid carcinoma,
head and neck cancer, carcinoid, mesothelioma, and hematological
malignancies, including CLL, MDS, multiple myeloma, and lymphomas. These
tumor types frequently are driven by angiogenesis or expression of
oncoproteins inhibited by sunititnib and as such are relevant to the
demonstration of proof of concept for sunitinib and other targeted agent
combinations. Tumors types specifically associated with constitutively
activated RTKs known to be inhibited by sunitinib include GIST (KIT),
glioma (PDGFR), and thyroid carcinoma (RET) (Krause *et al.*, 2005).

[**AZD0530** **(NSC 735464)**]{.underline}

**REQUEST FOR PHASE 2 TRIALS**

Letters of Intent due **[August 24, 2005]{.underline}**

**CONTACT:** John J. Wright, M.D., Ph.D. <wrightj@ctep.nci.nih.gov>

AZD0530 is a 5-, 7-substituted anilinoquinazoline molecule that is a
highly selective, orally available inhibitor of non-receptor tyrosine
kinases, which includes c-Src, c-Yes, Lck, and Bcr-Abl. AZD0530 is being
developed by CTEP as an anticancer agent in collaboration with
AstraZeneca Pharmaceuticals**.** CTEP is soliciting for single-agent
phase 2 trials of AZD0530 for the treatment of solid tumors including
**breast, non-small cell lung cancer, small cell lung cancer,
colorectal, pancreas, gastric/GEJ, prostate, ovary, melanoma, sarcoma,
and head and neck cancer.** Phase1 dose escalation studies are ongoing,
and an MTD for AZD0530 has yet to be established. All studies have been
orally administering AZD0530 on a once daily schedule.

[**VEGF Trap** **(NSC 724770)**]{.underline}

**Clinical trials**

**Preclinical experiments**

Letters of Intent due **July 6, 2005**

**CONTACT:** Alice Chen, M.D., <chenali@mail.nih.gov>.

VEGF Trap, an unique fusion protein combining the Fc portion of human
IgG~1~ with the principal extracellular ligand-binding domains of human
vascular endothelial growth factor receptor 1 (VEGFR1) and VEGFR
receptor 2 (VEGFR2), acts as a high-affinity soluble VEGF receptor and
potent angiogenesis inhibitor. VEGF Trap is being developed by CTEP as
an anticancer agent in collaboration with Sanofi-Aventis/Regeneron
Pharmaceuticals, Inc. CTEP is soliciting for proposal for Phase 2
clinical trial single-agent VEGF Trap in colorectal carcinoma, thyroid
carcinoma, bladder carcinoma, breast carcinoma, GYN sarcoma, melanoma,
MDS, AML, and myeloma.

In anticipation of future CTEP solicitation for other Phase 1/2 trials,
CTEP is also soliciting proposals for preclinical studies with VEGF
Trap. The primary goal of this solicitation is to identify areas for
further clinical investigation. Studies of interest include combinations
of VEGF Trap with direct clinical applicability, such as in combination
with cytotoxic chemotherapy, including those active in hypoxic
conditions, combinations of agents that target VEGF, targets within the
VEGF signaling pathway, targets within different pathways and agents
targeting components of different malignant processes.

**[E7389, Halichondrin B analog (NSC 707389)]{.underline}**

**Clinical trials**

**Preclinical experiments**

Letters of Intent due **May 18, 2005**

**CONTACT:** A. Dimitrios Colevas, M.D., <colevasa@ctep.nci.nih.gov>

CTEP is soliciting for phase 1 combination and phase 2 single-agent
clinical trials of E7389, a halichondrin B analogue tubulin
polymerization inhibitor. E7389 is being developed by CTEP in
collaboration with Eisai Research Institute (Eisai). E7389 is also
available for nonclinical studies via the NCI through a cooperative
agreement with Eisai. CTEP is specifically interested in experiments
that will generate data useful for prioritization of clinical
combination studies, mechanism of action studies, and studies to
evaluate radiation sensitization.

[**MLN518** **(NSC 726292)**]{.underline}

**REQUEST FOR PHASE 2 TRIALS**

Letters of Intent due **May 3, 2005**

Contact: John J. Wright, M.D., Ph.D., wrightj@ctep.nci.nih.gov

MLN518 (MW: 563, supplied as a sulfate salt), previously known as
CT53518, is a small molecule inhibitor of type III receptor tyrosine
kinases, which include FLT3, c-Kit, PDGFR, and CSF-1R. MLN518 is being
developed by CTEP as an anticancer agent in collaboration with
Millennium Pharmaceuticals Inc. CTEP is soliciting for single-agent
phase 2 trials of MLN518 for the treatment of **prostate** and **renal
cell carcinomas**, **glioblastoma**, and for patients with newly
diagnosed **acute myelogenous leukemia (AML)**:

#### [Aminoflavone Prodrug (AFP-464) NSC 710464]{.underline}

**Clinical trials**

Letters of Intent due **April 12, 2005**

CONTACT:Jennifer Low, M.D., Ph.D., e-mail:lowj@mail.nih.gov

CTEP is soliciting proposals for phase 1 single agent trials of the
aminoflavone prodrug (NSC 710464, AFP-464), a lysyl prodrug of
aminoflavone (NSC 686288, AF). AF is a flavone analog that has
differential activity in the 60-cell-line screen and marked antitumor
effect in mice bearing human tumor xenografts. In *in vitro* studies, AF
was cytotoxic in certain human renal and breast cancer cell lines, which
correlated with metabolization of AF by CYP1A1 and CYP1B1. These
metabolites covalently bind DNA and exert antiproliferative effects in
AF sensitive tumor cell lines. In these cells, AF was also shown to
induce CYP1A1 and CYP1B1 gene expression, via the aryl hydrocarbon
receptor (AhR) transduction pathway, a mechanism by which AF may induce
its own activation. Trial proposals should include a 3-hour infusion of
AFP-464 weekly schedule. Although nonclinical studies suggest that
modulatory activity is achieved at concentrations of approximately 1-2
μM, trial proposals should be designed to characterize the full toxicity
profile up to the maximum tolerated dose (MTD). Based on *in vivo*
toxicology studies, pulmonary toxicity may possibly be a significant and
dose limiting toxicity. In a dog study, pulmonary toxicity has been
observed with impaired diffusion lung capacity of carbon monoxide
(DL~CO~) that improved after stopping treatment. Thus, baseline and
continued serial monitoring of DL~CO~ should be incorporated into the
treatment monitoring plan. Patients with prior lung radiation therapy as
well as symptomatic pulmonary disease should be excluded from
participating in these studies.

**[SGN-30]{.underline}NSC# 731636**

**Clinical trials**

Letters of Intent due **April 4, 2005**

**CONTACT:** Thomas Davis, M.D.,
[davisth@mail.nih.gov](mailto:murgoa@ctep.nci.nih.gov)

The CD30 is a 105-120 kilodalton, integral membrane glycoprotein that is
a leukocyte activation marker and a member of the tumor necrosis factor
receptor (TNF-R) family. The expression of CD30 has been observed
primarily in activated T cells, B cells and natural killer cells, but
not in other human tissues (Wa*hl et a*l., 2002). It is over expressed
in malignancies such as Hodgkin's disease (HD), and anaplastic large
cell lymphoma (ALCL). Due to its expression profile, CD30 is an ideal
target for the treatment of HD and ALCL with monoclonal antibody (mAb)
based therapies. A mAb, AC10, against CD30 was shown to inhibit the
growth of HD cell lines *in vitro* (Bow*en et a*l., 1993). To generate a
clinically usable molecule for use in humans, the variable regions from
AC10 were cloned into an expression vector containing the human γ1 heavy
chain and κ light chain constant regions to obtain a genetically
engineered, chimeric antibody designated SGN-30. The chimeric antibody
retained the binding and *in vitro* growth-inhibitory properties of the
parental mAb (Wa*hl et a*l., 2002).

CTEP is soliciting for a limited number of Phase I or II studies that
will address specific questions related to this agent. Proposals for the
following studies will be considered for immediate approval. Proposals
for alternate studies will be considered but will only be approved if an
immediate compelling need is identified.

1)  Single agent mechanism of action/tumor targeting studies. The main
    goal of this approach is to characterize the binding of SGN-30 at
    the level of the tumor (tumor kinetics, saturation binding, etc.),
    particularly in heterogeneous tissues from HD and ALCL. Information
    from such studies will be used to inform decisions regarding dose
    and schedule of SGN-30, as well as ascertaining mechanisms of action
    and resistance. Studies in this category could include drug
    combinations with a single agent window design.

2)  Safety and activity of SGN-30 in combination with chemotherapeutic
    agents. This will be a multi-study program designed to evaluate the
    effectiveness of SGN-30 with established chemotherapy regimens used
    for relapsed and primary HD and ALCL, for example, SGN-30 with ABVD.
    Recognizing the difficulty of documenting that SGN-30 can augment
    the activity of frontline chemotherapy in these diseases, any
    measure of activity in pilot or phase 2 studies will need to
    incorporate some form of salvage endpoint, such as adding SGN-30 to
    chemotherapy for patients in the primary or secondary setting who
    are refractory to that chemotherapy.

3)  Safety and activity of SGN-30 in combination with novel biologically
    targeted agents. A compelling rationale or preclinical data
    supporting a high activity level in combination will be essential.