Apixaban or Dalteparin in Reducing Blood Clots in Patients With Cancer Related Venous Thromboembolism

PRIMARY OBJECTIVES:

I. Any episode of major bleeding including fatal bleeding.

SECONDARY OBJECTIVES:

I. Venous thromboembolism (VTE) recurrence including deep vein thrombosis (DVT), pulmonary
embolism (PE), fatal PE, or arterial thromboembolism.

II. Any episode of major bleeding including fatal bleeding or any episode of clinically
relevant non-major bleeding.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive apixaban 10 mg orally (PO) twice daily (BID) on days 1-7 and
lower-dose apixaban 5 mg PO BID on days 8-180.

ARM II: Patients receive dalteparin 200 international units (IU)/kg/day subcutaneously (SC)
once daily (QD) on days 1-30 and lower-dose dalteparin 150 IU/kg/day SC QD on days 31-180.

After completion of study treatment, patients are followed up at 3 months.

Inclusion Criteria:

- Confirmed acute lower extremity or upper extremity (jugular, innominate, subclavian,
axillary, brachial) DVT, PE, splanchnic (hepatic, portal, splenic, mesenteric, renal,
gonadal), or cerebral vein thrombosis

- Active cancer defined as metastatic disease and/or any evidence of cancer on
cross-sectional or positron emission tomography (PET) imaging, cancer related surgery,
chemotherapy or radiation therapy within the past 6 months; note: non-melanoma skin
cancer does not meet the cancer requirement

- Life expectancy >= 60 days

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2

- Obtained =< 30 days prior to randomization: Platelet count >= 50,000/mm^3

- Obtained =< 30 days prior to randomization: Alanine aminotransferase (ALT) or
aspartate transaminase (AST) =< 3 x upper limit of normal (ULN)

- Obtained =< 30 days prior to randomization: International normalized ratio (INR) =<
1.6 (if not taking anticoagulant therapy)

- Obtained =< 30 days prior to randomization: Calculated creatinine clearance must be >=
30 ml/min using the Cockcroft-Gault formula

- Negative serum or urine pregnancy test done =< 24 hours prior to randomization, for
women of childbearing potential only; note: a women of childbearing potential (WOCBP)
is defined as any female who has experienced menarche and who has not undergone
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not
postmenopausal; menopause is defined as 12 months of amenorrhea in a woman over age 45
years in the absence of other biological or physiological causes

- Ability to complete questionnaire(s) by themselves or with assistance

- Ability to provide informed written consent

- Willing to return to enrolling institution for follow-up (during the Active Monitoring
Phase of the study)

Exclusion Criteria:

- Any of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- Note: women of child bearing potential must agree to follow instructions for
method(s) of contraception for the duration of treatment with study drug (s)
plus 33 days after finishing the last dose

- Males who are sexually active with WOCBP must agree to follow instructions
for method(s) of contraception for the duration of treatment with study drug
(s) plus 93 days after finishing the last dose

- Azoospermic males and WOCBP who are continuously not heterosexually active
are exempt from contraceptive requirements; however they must still undergo
pregnancy testing as described in this section

- Note: investigators shall counsel WOCBP and male subjects who are sexually active with
WOCBP on the importance of pregnancy prevention and the implications of an unexpected
pregnancy Investigators shall advise WOCBP and male subjects who are sexually active
with WOCBP on the use of highly effective methods of contraception; highly effective
methods of contraception have a failure rate of < 1% when used consistently and
correctly

- At a minimum, subjects must agree to the use of one method of highly effective
contraception as listed below:

- HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

- Male condoms with spermicide

- Hormonal methods of contraception including combined oral contraceptive
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs)
such as Mirena by WOCBP subject or male subject?s WOCBP partner

- Female partners of male subjects participating in the study may use hormone
based contraceptives as one of the acceptable methods of contraception since
they will not be receiving study drug

- IUDs, such as ParaGard

- Tubal ligation

- Vasectomy

- Complete abstinence

- Complete abstinence is defined as complete avoidance of heterosexual
intercourse and is an acceptable form of contraception for all study
drugs; female subjects must continue to have pregnancy tests;
acceptable alternate methods of highly effective contraception must be
discussed in the event that the subject chooses to forego complete
abstinence

- Treatment with an anticoagulant for more than 7 days for the current blood clot, prior
to randomization

- Active bleeding

- Severe hypersensitivity reaction to apixaban, dalteparin, heparin or pork products
(e.g., anaphylactic reactions)

- Use of the following CYP3A4 inducers: rifampin, rifabutin, carbamazepine, efavirenz,
phenobarbital, phenytoin, fosphenytoin, primidone, and St. John?s wort)

- Thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor) that will be continued
on study

- Severe liver disease (known cirrhosis Childs Pugh class B or C), or active hepatitis

- Use of a Factor Xa inhibitor (e.g. apixaban, rivaroxaban, or edoxaban) =< 3 months
prior to randomization

- Treatment of a thromboembolic event =< 6 months prior to randomization

- Documented venous thromboembolism while on therapeutic anticoagulation
(?anticoagulation failure?)

- Mechanical heart valve

- Documented hemorrhagic tendencies

- Bacterial endocarditis

- History of heparin induced thrombocytopenia

- Any of the following conditions:

- Intracranial bleeding =< 6 months prior to randomization

- Intraocular bleeding =< 6 months prior to randomization

- Gastrointestinal bleeding and/or endoscopically proven ulcer =< 6 months prior to
randomization

- Head trauma or major trauma =<1 month prior to randomization

- Neurosurgery =< 2 weeks prior to randomization

- Major surgery =< 1 week prior to randomization

- Overt major bleeding at the time of randomization

- Gross hematuria at the time of randomization