A PHASE 1 TRIAL OF PF-03084014 IN PATIENTS WITH ADVANCED SOLID TUMOR MALIGNANCY AND T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOBLASTIC LYMPHOMA
The goal of Part 1 of this clinical research study is to learn if PF-03084014 will have an effect on T-cell acute lymphoblastic leukemia or lymphoblastic leukemia. The goal of Part 2 of this study is to learn if PF-03084014 when given in combination with dexamethasone will have an effect on T-cell acute lymphoblastic leukemia or lymphoblastic leukemia. The safety and tolerability of this PF-03084014 will be tests in both parts.
Disease Group: Leukemia
Treatment Agent: PF-03084014
Treatment Location: Both at MD Anderson & Other Sites
Primary Objectives 1. To determine the maximum tolerated dose (MTD) of PF-03084014 when administered twice daily for 21 days alone in patients with advanced malignancies.(encompassing advanced solid tumors and relapsed or refractory T-ALL/LBL). Phase 1a Secondary Objectives 1. To evaluate the safety and tolerability of PF-03084014 when administered twice daily for 21 days in patients with relaspsed or refractory T-ALL/LBL. 2. To characterize single-dose and multiple-dose pharmacokinetics (PK) of PF-03084014 including the effect of food on PK, in patients withrelaspsed or refractory T-ALL/LBL. 3. To evaluate the pharmacodynamics of PF-03084014 in patients with advanced malignancies. 4. To document any anti-tumor activity with PF-03084014 alone in patients with relaspsed or refractory T-ALL/LBL.. 5. To characterize the effects of PF-03084014 on QTc. 6. To evaluate mechanisms of sensitivity and resistance to PF-03084014 in patients with advanced malignancies.
IRB Review and Approval Date: 12/01/2011
Recruitment Status: Not Accepting
Projected Accrual: 60
1) Patients with advanced solid tumor malignancy (with measurable
disease as per Recist for patients enrolled in the expansion cohort)
that is resistant to standard therapy or for which no standard therapy
2) Patients with acute T-ALL/LBL that are refractory/resistant to current treatment options or for which no standard therapy is available. T-ALL/LBL disease is defined as: Leukemia or lymphoma cells must express at least 2 of the following cell surface antigens: CD1a, CD2, CD3 (surface or cytoplasmic), CD4, CD5, CD7, and CD8. Leukemia cells must be negative for myeloperoxidase histochemical stains; If the only T cell markers present are CD4 and CD7, the leukemia cells must also lack the myeloid markers CD33 and/or CD13. Patients with less than or equal to 25% lymphoblasts in the bone marrow either at initial diagnosis or at study entry are considered to have T-ALL. Patients with less than or greater than 25% lymphoblasts in the bone marrow either at initial diagnosis or at study entry are considered to have T-LBL.
3) Patient is >3 weeks (advanced solid tumor malignancy) or >2 weeks (T-ALL/LBL) from last anti-cancer treatment (except Hydrea, and intrathecal prophylaxis in T-ALL/LBL population) at study entry and all acute adverse events of any prior therapy have resolved or, if persisting, are not considered to be clinically important.
4) Patient is >2 months from allogenic hematopoietic stem cell transplant or 30 days from autologous stem cell transplant and the patient has recovered from transplant associated toxicities prior to the first dose of study drug.
5) Men and women greater or equal to 16 years old.
6) ECOG performance status of 0,1 or 2 for patients with refractory or relapsed T-ALL/LBL.
7) Creatinine clearance greater than or equal to 50 ml/min as collected using the method standard for the institution.(examples include but are not limited to Cockcroft-Gault or Modification of Diet in Renal Disease [MDRD]).
8) Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) less than or equal to 2.5 x upper limit of normal (ULN), or AST and ALT less than or equal to 5 x ULN if liver function abnormalities are due to underlying malignancy.
9) Total serum bilirubin is less than or equal to 1.5 x ULN (except patients with documented Gilbert’s syndrome).
10) For patients with advanced solid tumor malignancy: Absolute neutrophil count (ANC) is greater or equal to1500/uL; Platelets are greater or equal to 100,000/uL independent of transfusions; Hemoglobin greater or equal to 9.0 g/dL independent of transfusions.
11) Urinary protein <2+ by dipstick. If dipstick greater than or equal to 2+, then a 24-hour urine collection can be done and the patient may enter only if urinary protein is <2 g/24 hour.
12) Signed and dated written informed consent indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
13) Willingness and ability to comply with the study scheduled visits, treatment plans, laboratory tests and other procedures.
14) Life expectancy >2 months.
1) Prior treatment with a gamma secretase inhibitor or and anti-Notch
receptor antibody for treatment of cancer.
2) Concurrent therapy with a gamma secretase inhibitor or other investigational or approved agents for malignancy beyond the scope of this trial.
3) Patients with clinical evidence of CNS disease or known CNS disease.
4) Patients taking Tamoxifen.
5) Active graft versus host disease (GVHD) with other than grade 1 involvement at any organ site.
6) Patients taking immunosuppressants for treatment of GVHD. Patient must be greater or equal to 2 weeks from last dose of any immunosuppressive medication
7) Known malabsorption syndrome or other condition that may impair absorption of study medication (eg, gastric bypass or lap band).
8) Current drug or alcohol abuse.
9) QTc interval of >470 msec.
10) Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
11) Patients with active uncontrolled bacterial, fungal or viral infection.
12) Patients with active hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
13) Patient with history of any malignancy (other than nonmelanoma skin cancer) excluding current cancer diagnosis, within the past 5 years who is thought to have a significant risk of relapse at the start of the current trial by their physician.
14) Current use or anticipated need for food or drugs that are known strong and/or moderate CYP3A4 inhibitors, including their administration within 14-days prior to the first PF-03084014 dose (ie, Strong CYP3A4 Inhibitors: grapefruit juice or grapefruit/grapefruit related citrus fruits [eg, Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan; Moderate CYP3A4 inhibitors: Erythromycin, verapamil, atazanavir, delavirdine, fluconazole, darunavir, diltiazem, aprepitant, imatinib, tofisopam, ciprofloxacin, cimetadine).
15) Current use or anticipated need for drugs that are known strong CYP3A4 inducers, including their administration within 14-days prior to the first PF-03084014 dose (ie, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, clevidipine, St. John’s Wort).
16) Concurrent administration of herbal preparations (unless with sponsor approval).
17) Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or in the judgment of the investigator would make the patient inappropriate for entry into the study.
18) Pregnancy or breast feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test within 7 days of starting treatment. Males and females of childbearing potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for 90 days (female) and 6 months (male) after last dose of investigational product. A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
19) Major Surgery within 4 Weeks (or 28 days) of treatment.
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