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Abstract

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Gemcitabine has modest antitumor activity in advanced pancreatic cancer. New agents are clearly needed. Pemetrexed (ALIMTA®) is a novel antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed has shown in vitro activity against pancreatic cancer cell lines. In a Phase I trial of pemetrexed, two patients with pancreatic cancer achieved partial responses on the once every 21 days schedule. A Phase II trial of pemetrexed in patients with advanced pancreatic cancer showed an objective response rate of 6%, a one year survival of 28%, and a mild toxicity profile. The combination of pemetrexed and gemcitabine is synergistic in vitro and was broadly active in a Phase I trial. The pemetrexed/gemcitabine combination was evaluated in a Phase II trial in 42 patients with advanced pancreatic cancer. The promising activity observed in this study has led to an ongoing international, randomized, Phase III trial in 520 patients comparing the pemetrexed/gemcitabine combination with gemcitabine alone. Cancer 2002;95:928–32. © 2002 American Cancer Society.

DOI 10.1002/cncr.10755

Over 29,000 Americans developed cancer of the pancreas in 2001.1 Only 1–4% of all patients with pancreatic cancer will survive five years, making it the fourth leading cause of cancer death in the United States.1 Long term survival is limited to those individuals who have resectable tumors. Since symptoms usually develop late, more than 80% of patients present with locally advanced or metastatic disease; their survival is usually measured in months.2

Few chemotherapeutic agents produce objective responses in patients with pancreatic cancer. Between 1991 and 1994, 25 new investigational agents were evaluated in Phase II clinical trials. The median response rate was 0% (range, 0–14%), and the median survival observed was three months.3 Clearly, novel active agents are needed.

Single agent gemcitabine is currently the chemotherapy standard of care for patients with advanced pancreatic cancer. However, response rates are modest. In the initial Phase II trial of 44 patients reported by Casper et al., 11% of patients had an objective response, but a subset of patients experienced a clinical benefit response that consisted of an improvement in pain as reflected by analgesic consumption, pain intensity, and improvement in performance status (PS).4 A subsequent randomized Phase III trial (n = 126) by Burris et al. compared gemcitabine to weekly 5-fluorouracil (5-FU). Patients who received gemcitabine experienced clinical benefits and achieved a modest survival advantage over those patients treated with 5-FU.5 Treatment with gemcitabine yielded an objective tumor response rate of 5.4%, a clinical benefit response of 23.8%, and a one year survival of 18%, compared with an objective tumor response rate of 0%, a clinical benefit response rate of 4.8%, and a one year survival of 2% for 5-FU.

The symptomatic benefit achieved with gemcitabine and its mild toxicity profile have prompted numerous investigators to combine other agents with gemcitabine in an effort to enhance its activity.2

Pemetrexed (ALIMTA®)

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Pemetrexed (ALIMTA®; N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid; Eli Lilly and Company, Indianapolis, IN) is a novel pyrrolopyrimidine-based antifolate.6 Pemetrexed enters cells via the reduced folate carrier and undergoes intracellular polyglutamation, resulting in prolonged intracellular retention.7 Pemetrexed and its polyglutamated metabolites inhibit several key folate-requiring enzymes, including thymidylate synthase (TS), dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and aminoimidazole carboxamide ribonucleotide formyltransferase.7, 8 Three of these pathways are illustrated in Figure 1. The cytotoxicity of pemetrexed is thought to be primarily mediated through TS inhibition.8 However, inhibition of the other folate enzymes may also be important, since pemetrexed is active against human cancer cell lines that are resistant to raltitrexed and 5-FU due to TS amplification.9 Pemetrexed shows significant activity against a broad spectrum of tumors in a variety of in vitro tumor models, including pancreatic cancer cell lines (generally considered chemoresistant) in the human tumor cloning assay.10

Phase I Trials of Single Agent Pemetrexed

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Three Phase I studies of pemetrexed have been conducted using three different schedules of administration: once every 21 days; weekly for 4 weeks every 42 days; and daily for 5 days every 21 days. Table 1 summarizes these studies.

Table 1. Phase I Trials of Pemetrexed
AuthorScheduleNo. of patientsMTDDLTPartial responsesMinor responses
  1. MTD: Maximum tolerated dose; DLT: dose-limiting toxicity; NSCLC: nonsmall-cell lung cancer.

McDonald11daily × 5 every 21 days384 mg/m2/dneutropenia, elevated liver enzymesNoneOne NSCLC one colorectal cancer
Rinaldi12weekly × 4 every 42 days2540 mg/m2/wkneutropeniaNonetwo colorectal cancer
Rinaldi13once every 21 days37600 mg/m2neutropenia, thrombocytopenia, fatiguetwo pancreatic cancer two colorectal cancersix colorectal cancer

McDonald et al. administered a total of 116 cycles daily for 5 days every 21 days to 38 patients with advanced malignancies refractory or not amenable to conventional therapy. Ten dose levels were evaluated, ranging from 0.2 to 5.2 mg/m2/d. Dose limiting toxicities (DLTs) included neutropenia and reversible elevations of hepatic enzymes. The maximum tolerated dose (MTD) was 4.0 mg/m2/d. Minor responses were achieved in two patients, one each with nonsmall cell lung cancer and colorectal cancer.11

Fifty eight courses of pemetrexed were administered to the 25 patients who received the weekly for 4 weeks every 42 days schedule, as reported by Rinaldi et al. Doses ranged from 10 to 40 mg/m2/wk. Neutropenia was dose-limiting at 40 mg/m2/week. Minor responses were noted in two patients with colorectal cancer.12

The same group of investigators also treated 37 patients on the once every 21 days schedule. A total of 132 courses of pemetrexed were administered at nine dose levels, ranging from 50–700 mg/m2. The MTD was 600 mg/m2, and DLTs were neutropenia, thrombocytopenia, and cumulative fatigue. Other toxicities included rash, mucositis, and elevations of hepatic transaminases. Partial responses were observed in two patients with pancreatic cancer and in two colorectal cancer patients. Six minor responses were noted in patients with colorectal cancer. Three of the four patients who achieved partial responses in this trial had failed prior treatment with a TS inhibitor.13

The once every 21 days schedule, which permitted the highest dose intensity with the most acceptable toxicity profile, was selected for Phase II evaluation.

Phase II Trial of Pemetrexed in Pancreatic Cancer

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

The two partial responses observed in the Phase I trial of pemetrexed on the every 21 day schedule prompted Miller et al. to evaluate the activity of pemetrexed in a Phase II trial involving 42 previously untreated patients with advanced pancreatic cancer.14 Patients received 600 mg/m2 of pemetrexed via a 10 minute intravenous (IV) infusion once every 21 days. Most patients (79%) had metastases; 21% had locally advanced unresectable disease. The median age was 60.3 years (range, 37 to 77). A total of 57% of the patients were male. Eastern Cooperative Oncology Group PS was 0 in 32% of patients, 1 in 51%, and 2 in 17%. All patients were evaluable for toxicity; 35 patients received at least two doses of chemotherapy and were evaluable for response. Clinical benefit response was not assessed. This study is summarized in Table 2.

Table 2. Phase II Trial of Single Agent Pemetrexed in Pancreatic Cancer14
FeatureMeasure
No. of Patients42
Dose/Schedule600 mg/m2 every 21 days
Vitamin supplementationNone
Complete responses1
Partial responses1
Overall response rate5.7%
Stable disease40%
One year survival28%
Median survival6.5 months

The overall response rate in evaluable patients was 5.7%, with one complete response (lasting 16.2 months) and one partial response (lasting 6.9 months). Stable disease was achieved in 40% of evaluable patients (n = 17), including five who maintained stable disease for more than six months. The 1 year survival was 28%, median survival 6.5 months, and median progression free survival 4 months (95% confidence interval [CI], 1.6–4.7 months).

Although Grade 3/4 neutropenia was observed in 41% of patients, no infections greater than Grade 1 developed. Other Grade 3/4 hematologic toxicities included thrombocytopenia and anemia in 17% and 19% of patients, respectively. Nonhematologic Grade 3/4 toxicities included rash in 10% of patients, nausea in 17%, mucositis in 7%, and fatigue in 19%. Only one patient developed alopecia. Grade 3/4 alanine aminotransferase and aspartate aminotransferase elevations were observed in 7% and 15% of patients, respectively.

The Pemetrexed/Gemcitabine Combination

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Pemetrexed and gemcitabine are synergistic in human tumor xenograft models.15 Using in vitro clonogenic assays, Adjei et al. reported cytotoxic synergy when gemcitabine was administered prior to pemetrexed in human HCT-8 colon cancer cell lines.16 Other investigators have shown cytotoxic synergy for the opposite sequence, pemetrexed followed 24 hours later by gemcitabine, in HT29 colon cancer cell lines and xenografts.17 These data suggest that patterns of interaction between gemcitabine and pemetrexed may be cell line specific.

The synergy observed with gemcitabine and pemetrexed in vitro led Adjei et al. to perform a Phase I trial of the gemcitabine/pemetrexed combination in patients with advanced solid tumors.18 Gemcitabine was administered at doses of 1000 or 1250 mg/m2 IV over 30 minutes on Days 1 and 8 of a 21 day cycle. Pemetrexed was delivered 90 minutes later in escalating dose levels of 200, 300, 400, 500, and 600 mg/m2 on Day 1 of a 21 day cycle (Group I). Since neutropenia that developed on Day 8 led to reduction or omission of the gemcitabine dose in more than 57% of treatment courses, a second group of patients (Group II) received pemetrexed on Day 8. The results of this trial are summarized in Table 3.

Table 3. Phase I Trial of Pemetrexed Plus Gemcitabine in Patients with Advanced Solid Tumors18
FeatureGroup IGroup II
Patients3421
Cycles16485
Vitamin supplementationNoneNone
Maximum tolerated doseGemcitabine 1000 mg/m2 Days 1 and 8 Pemetrexed 500 mg/m2 Day 1Gemcitabine 1250 mg/m2 Days 1 and 8 Pemetrexed 500 mg/m2 Day 8
Dose limiting toxicityNeutropeniaNeutropenia
Partial responses12: 3 colorectal cancer, 3 nonsmall cell lung cancer, 2 cholangiocarcinoma, 2 ovarian cancer, 1 mesothelioma, 1 breast cancer

In Group I, 35 patients received 164 cycles of pemetrexed/gemcitabine. Twenty one patients in Group II received 85 cycles of chemotherapy. Neutropenia was dose limiting. Other toxicities included rash, fatigue, and increased transaminases. The recommended Phase II doses were 1250 mg/m2 of gemcitabine on Days 1 and 8 and 500 mg/m2 of pemetrexed given on Day 8. This combination showed activity in a broad range of tumors. There were 12 partial responses in the 35 evaluable patients. Pharmacokinetic analysis determined that prior administration of gemcitabine did not alter the disposition of pemetrexed.

Vitamin Supplementation in Pemetrexed Trials

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Folic acid administered with pemetrexed preserves antitumor activity and reduces toxicity in human tumor cell lines and in tumor bearing mice.19 A very sensitive marker of folate status is plasma homocysteine. In multivariate analysis, a baseline homocysteine level ≥ 12 μM is a predictor of Grade 3/4 pemetrexed toxicities, including diarrhea, rash, neutropenia, thrombocytopenia, mucositis, and fatigue.20 Supplementation with dietary levels of folate and B12 significantly decreases toxicities related to pemetrexed.19 Since November 1999, all patients on pemetrexed trials have received oral supplementation with 350-1000 μg of folic acid daily and 1000 μg B12 intramuscularly every nine weeks beginning at least one week prior to chemotherapy and continuing throughout treatment. It is thought that supplementation of folic acid at a level equivalent to an American diet should not affect the efficacy of pemetrexed. B12 is required for the 15% of patients who are B12-deficient.

Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Given the known, albeit modest, activity of both gemcitabine and pemetrexed in pancreatic cancer, the in vitro synergy of the two agents, and the broad activity of the combination observed in the Phase I trial, Kindler et al. initiated a multicenter Phase II trial of gemcitabine plus pemetrexed in September 1999. The trial enrolled 42 previously untreated patients with histologically proven, locally advanced or metastatic pancreatic cancer. Patients were required to have a Karnofsky PS of at least 60%, a life expectancy of 12 weeks, bidimensionally measurable disease, and normal hematologic, hepatic, and renal function.

Patients received gemcitabine 1250 mg/m2 by IV infusion over 30 minutes on Days 1 and 8 of a 21 day cycle. Pemetrexed 500 mg/m2 was administered by IV infusion over 10 minutes on Day 8, 90 minutes after gemcitabine. All patients received premedication with dexamethasone to prevent rash. In November 1999, when safety data determined that toxicity could be prevented with folate and B12 supplementation, all patients were administered dietary levels of these vitamins. Computed tomography scans were obtained every two cycles to assess for response. Clinical benefit response, assessed by changes in pain, PS, or weight change, was monitored weekly.

The results of this trial will be presented at the 2002 Meeting of the American Society of Clinical Oncology.

Phase III Trial of Pemetrexed/Gemcitabine

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Promising results obtained in the Phase II trial of the combination of pemetrexed plus gemcitabine led to the development of an ongoing Phase III international trial in 520 patients. Previously untreated patients with locally advanced or metastatic pancreatic cancer are randomized by PS, disease stage, investigational center, and baseline homocysteine level to one of two treatment regimens: gemcitabine 1,000 mg/m2 by IV infusion weekly on Days 1, 8, and 15 every 28 days, or gemcitabine 1,250 mg/m2 by IV infusion on Days 1 and 8 of a 21 day cycle plus pemetrexed 500 mg/m2 by IV infusion on Day 8. Patients on the combination arm also receive vitamin supplementation with folate and B12. End points include overall survival, progression free survival, objective response rate, quality of life, and toxicity.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES

Pemetrexed, a new generation antifolate antimetabolite, has activity in pancreatic cancer. The 6% response rate, while modest, is similar to other single agents in previously untreated patients with this disease, while the 28% one year survival is promising. Pemetrexed is synergistic with gemcitabine in vitro, and the combination of these two drugs was broadly active and well tolerated in a Phase I study. The pemetrexed/gemcitabine combination has been evaluated in a recently completed Phase II trial. An ongoing Phase III trial that compares the combination of pemetrexed/gemcitabine to single agent gemcitabine will help to determine whether this combination improves survival and quality of life for patients with advanced pancreatic cancer.

REFERENCES

  1. Top of page
  2. Abstract
  3. Pemetrexed (ALIMTA®)
  4. Phase I Trials of Single Agent Pemetrexed
  5. Phase II Trial of Pemetrexed in Pancreatic Cancer
  6. The Pemetrexed/Gemcitabine Combination
  7. Vitamin Supplementation in Pemetrexed Trials
  8. Phase II Trial of Pemetrexed/Gemcitabine in Pancreatic Cancer
  9. Phase III Trial of Pemetrexed/Gemcitabine
  10. CONCLUSIONS
  11. REFERENCES
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  • 12
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    Worzalla JF, Shih C, Schultz RM. Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res. 1998; 18: 32353239.
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