A Phase I Study of OSI-906 in Combination With Pemetrexed in Advanced Solid Tumor Malignancies

OSI-906 is a new agent that inhibits the insulin-like growth factor receptor pathway.
Targeting this pathway appears to be a promising strategy to treat cancer based on
laboratory studies. The present study will test if this agent can be administered safely in
combination with pemetrexed, a commonly used chemotherapeutic agent.

Inclusion Criteria:

- Both men and women of all races and ethnic groups are eligible for this trial.

- Patients must have histologically confirmed malignancy.

- Patient's tumor type must be appropriate for therapy with pemetrexed or have no
standard treatment approaches.

- Patients must have discontinued previous chemotherapy and/or radiation at least 3
weeks[six weeks for nitrosoureas, BCNU, or mitomycin C] prior to entry into the study
and recovered from any toxic effects of previous treatment. Pallative radiation
therapy to sites involving more than 2 weeks prior to enrollment on this study.

- Age greater than 18 years.

- ECOG performance status less than 2 [see Appendix A].

- Patients should be able to take oral medications.

- Patients must have normal organ and marrow function as defined below:

- leukocytes greater than 3,000/mcL

- absolute neutrophil count greater than 1,500/mcL

- platelets greater than 100,000/mcL

- total bilirubin within normal institutional limits AST[SGOT]/ALT[SGPT]less than 2.5 x
institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance greater than 60 mL/min/1.73 m2 for patients with creatinine
levels above institutional normal.

- The effects of OSI-906 on the developing human fetus are unknown. For this reason
and because chemotherapeutic agents as well as other therapeutic agents used in this
trial are known to be teratogenic, 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 and for the duration of study participation. 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.

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

Exclusion Criteria:

- Patients may not be receiving any other investigational agents.

- Patients with untreated, active or symptomatic brain metastases should be excluded
from this clinical trial.

- History of allergic reaction to OSI-906 or pemetrexed.

- 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 adherence with
study requirements.

- Pregnant women are excluded from this study because OSI-906 and pemetrexed are
anti-proliferative agents agent with the potential for teratogenic or abortifacient
effects. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with OSI-906, breastfeeding
should be discontinued if the mother is treated OSI-906. These potential risks may
also apply to other agents used in this study.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with OSI-906. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.

- Patients with QTc interval greater than 450 msec at baseline will be excluded due to
risk of QTc prolongation with OSI-906.

- Patients taking medications that prolong the QTc interval will be excluded.

- Patients with significant cardiac disease will be excluded.

- Patients with fasting blood glucose greater than 150 mg/dL at baseline will be
excluded due to risk of hyperglycemia with OSI-906.

- Use of drugs that have a known risk of causing Torsades de Pointes [TdP] [Torsades
List on www.azcert.org/medical-pros/drug-lists/bycategory.cfm, see Appendix D] are
prohibited within 14 days prior to randomization.

- Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent
CYP1A2 inhibitors/inducers are not excluded.

- Patients with a history of poorly controlled gastrointestinal disorders that could
affect the absorption of study drug (eg, Crohn's disease, ulcerative colitis, etc)
should be excluded.