Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy

A Randomized, Double-Blinded, Placebo Controlled Phase III Trial Using Acetyl-L-Carnitine(ALC)(NSC# 747431) for the Prevention of Chemotherapy-Induced Peripheral Neuropathy in Patients With Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancer

This randomized phase III trial studies how well acetyl-L-carnitine hydrochloride works compared to a placebo in preventing peripheral neuropathy in patients with recurrent ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer undergoing chemotherapy. Acetyl-L-carnitine hydrochloride may prevent or lessen peripheral neuropathy caused by chemotherapy. It is not yet known whether acetyl-L-carnitine hydrochloride is more effective compared to a placebo in preventing peripheral neuropathy caused by chemotherapy.

PRIMARY OBJECTIVES:

I. Evaluate the therapeutic efficacy of acetyl-L-carnitine hydrochloride (ALC) in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.

SECONDARY OBJECTIVES:

I. Evaluate the effect of ALC on chemotherapy-induced fatigue based upon the Functional Assessment of Cancer Therapy (FACT)-Fatigue scale.

II. Evaluate the effect of ALC on sensory peripheral neuropathy as measured with the first 4 items of the FACT/Gynecologic Oncology Group (GOG)-Neurotoxicity (Ntx) subscale (FACT/GOG-Ntx_4 subscale).

III. Evaluate the effect of ALC on the health-related quality of life as measured by the FACT-Ovarian (O) trial outcome index (TOI).

OUTLINE: This is a multicenter study. Patients are stratified according to planned dosage of paclitaxel (< 150 mg/m^2 vs ≥ 150 mg/m^2), and age (< 60 years of age vs ≥ 6 years of age). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive acetyl-L-carnitine hydrochloride (ALC) orally (PO) twice daily (BID) on days 1-21 (during chemotherapy treatment).

ARM II: Patients receive placebo PO BID on days 1-21 (during chemotherapy treatment) (maximum of 8 courses).

In both arms, treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients also complete questionnaires comprising the Functional Assessment of Cancer Therapy (FACT)-Fatigue scale, the FACT-Gynecologic Oncology Group Neurotoxicity subscale (FACT/GOG-Ntx_4 subscale), and the FACT-Ovarian trial outcome index (FACT-O TOI) at baseline, prior to courses 3 and 5, within 4 weeks after completion of treatment, and then at 3 months after completion of treatment.

Inclusion Criteria:

• Patients must have histologic diagnosis of epithelial ovarian carcinoma, peritoneal primary or fallopian tube carcinoma, which is now recurrent

• Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner tumor, or adenocarcinoma not otherwise specified (N.O.S.)

• All patients must have had a treatment-free interval without clinical evidence of progressive disease of at least 6 months from completion of front-line chemotherapy (both platinum and taxane); front-line therapy may have included a biologic agent (i.e., bevacizumab)

  • Front-line treatment may include maintenance therapy following complete clinical or pathological response; however, maintenance cytotoxic chemotherapy must be discontinued for a minimum of 6 months prior to documentation of recurrent disease; patients receiving maintenance biological therapy or hormonal therapy are ELIGIBLE provided their recurrence is documented more than 6 months from primary cytotoxic chemotherapy completion (includes maintenance chemotherapy) AND a minimum 4 weeks has elapsed since their last infusion of biological therapy

  • Patients receiving hormonal therapy for biochemical or non-measurable recurrence disease are ELIGIBLE provided their recurrence is documented more than 6 months following the completion of primary cytotoxic chemotherapy; a minimum of 4 weeks must have expired since their last exposure to hormonal therapy

    • The complete response to front-line chemotherapy must have included a negative physical exam, normalization of CA125 if elevated at baseline, and negative radiographic assessment of disease, if obtained
    • Patients who have undergone reassessment laparotomy or laparoscopy following primary therapy are eligible for this study as long as they demonstrated a pathologic complete response based on the surgical assessment (i.e. all obtained specimens were histologically negative for disease)

• Patients with a past history of primary endometrial cancer within the last five years are excluded unless all of the following conditions are met:

  • Stage not greater than IB
  • No more than superficial myometrial invasion, without vascular or lymphatic invasion
  • No poorly differentiated subtypes, including papillary serous, clear cell, or other International Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions

• Patients must be expected to receive a minimum of 2 cycles of paclitaxel and a platinating agent for their recurrent disease;

  • Addition of other drugs such as bevacizumab is acceptable as long as these additional drugs are not typically associated with peripheral neuropathy
  • The initial, planned infusion duration of each dose of paclitaxel must be 3 hours or less

• Patients must start the study with a GOG performance status of 2 or less

• Serum creatinine ≤ 2.5 mg/dL

• Neuropathy (sensory and motor) less than or equal to the National Cancer Institute (NCI) CTCAE v4.0 grade 1

• No patients with a history of seizure activity

• No patients who are unable to swallow oral medications

• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years

• No patients of childbearing potential not practicing adequate contraception

• No patients who are pregnant or nursing

• No patients who are known to have diabetes

• No patients with known allergies to ALC (acetyl-L-carnitine hydrochloride)

• Patients are excluded if their previous cancer treatment contraindicates this protocol therapy

• No patients who have received more than one previous regimen of chemotherapy (maintenance is not considered a second regimen)

• No patients receiving concurrent immunotherapy or radiotherapy

• No patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis

• No patients who are currently receiving or have received warfarin or acenocoumarol within the past 7 days

• No patients taking > 100 units of racemic vitamin E (or > 50 units of ααα-tocopherol) daily within 5 days of starting study therapy

• No patients taking other medications (Rx, OTC, or dietary supplements) to prevent or treat neuropathy within 5 days of starting study treatment; such products include:

  • Gabapentin (Neurontin ®)
  • Pregabalin (Lyrica ®)
  • Duloxetine (Cymbalta ®)
  • Alpha-lipoic acid
  • Note that tricyclic antidepressants or selective serotonin/norepinephrine-selective reuptake inhibitors prescribed for the treatment of mood disorders are allowed