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Clinical Trials

Listed here are selected clinical trials for CLL that have been announced within the last 18 months.
Some of these may still be recruiting patients.
For more information, please contact the cancer center or sponsor mentioned in each announcement or consult the NCI and NIH Clinical Trials Databases from the link on our Search Tools page.

 

:  Rituxan + HDMP Clinical Trial Update

Correspondence with Dr. Thomas Kipps

Current Status of Trial -  Detailed Inclusion and Exclusion Criteria

We thank Dr. Kipps for responding to our query regarding the status of this trial. You can read the correspondence in Rituxan + HDMP Update.

:  FluCam 106

Combination Therapy with Fludarabine and Campath

Berlex Labs Recruiting Participants for Phase 2 Multi-center Clinical Trial Supervised by John Gribben

We report on our participation in a Patient Advisory Board Meeting conducted by Berlex Laboratories, US distributors for Campath and fludarabine. FluCam 106 is a direct head-to-head comparison between Campath + fludarabine versus the better understood Rituxan + fludarabine therapy pioneered by Byrd, et. al. Campath plus fludarabine is a powerful combination of agents that has proven effective even in cases refractory to fludarabine and Campath as single agents. This is an important clinical trial and we examine the issues involved.

:  New Drug in Clinical Trial

Novel Application of a New Anti-CD25 Immunotoxin Offers Prospects of Highly Targeted and Effective Therapy

LMB-2 in Phase -II Trial Sponsored by NCI

We report on the recently announced clinical trial of a new immunotoxin, LMB-2,  which shows early promise in attacking CLL cells. The technology has great potential if it is used in combination with immunomodulators such as bacterial-DNA derived CpG-ODN to up-regulate CD25, improving targeting of B-CLL cells. We discuss the background, results from early trials and the potential for effective treatment with low toxicity using this agent. Read about it in LMB-2.

The following are generally shorter articles, all presented together on this page.

: Pentostatin + Cyclophosphamide + Rituxan Trial at Mayo Clinic

: Rituxan plus PT-100 Phase I Clinical Trial

: New Genasense Trial

: Genasense and Rituxan Combination - Phase II Clinical Trial for NHL

: Genasense Phase I/II Clinical Trial

: Thalidomide - Phase II Clinical Trial Locations

: Announcement of Genasense Trial


Announcement of Genasense Trial         

4/29/02

by Chaya Venkat

This trial employs Genasense, Fludarabine and Cyclophosphamide. More information may be available from WPCI at the number given below; and a lot more information about Genasense from Genta Incorporated (Nasdaq: GNTA), the manufacturer. Their website is at http://www.genta.com.

Genasense is an elegant approach to removing the resistance of CLL cells to dying a normal death. I will try and get out an article on Genasense in the next few days.

Press Release:

"The present approach to chronic lymphocytic leukemia is to treat with drugs such as fludarabine, oral fludarabine plus cyclophosphamide plus or minus Rituxan. Many patients achieve meaningful responses; however, complete remissions are unusual. Progressive disease is treated with various drug combinations often with shorter periods of remission. A new approach employs the use of Genasense (Bc1-2 antisense oligonucleotide) for therapy. By blocking or reducing Bc1-2 expression, cells become apoptotic and lead to programmed cell death. It is believed that certain lymphoid malignancies continue to grow and indeed are resistant to certain treatment modalities because of excessive Bc1-2 expression. Blockade of this expression would be expected to pro-apoptotic i.e., to induce leukemia-cell death and thereby lead to remission. Treatment with this antisense molecule is now available for patients who have received prior therapy with other agents. They will be randomized to receive fludarabine and cyclophosphamide alone or fludarabine and cyclophosphamide with the addition of Genasense. Therapy will be repeated every 28 days for a maximum of 6 Cycles. (April 2001)" 

"This study has recently opened for enrollment at The Western Pennsylvania Cancer Institute at The Western Pennsylvania Hospital. Call 1-800-860-WPCI for more information or to become enrolled in a trial."

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Thalidomide - Phase II Clinical Trial Locations        

6/12/02

by Chaya Venkat

Details of the protocol for a Phase - II clinical trial using Thalidomide that is currently open at Mayo Clinic, and recruiting CLL patients are available by clicking . 

The Thalidomide based clinical trial for CLL now seems to be a very large multi-center effort. Below is a lot more information on where all this therapy is being evaluated. You will have to call the contact numbers provided to get specific details. 

Announcement:

Thalidomide in Patients With Relapsed Chronic Lymphocytic Leukemia

This study is currently recruiting patients.

Sponsored by National Cancer Institute (NCI) North Central Cancer Treatment Group

RATIONALE: Thalidomide may stop the growth of chronic lymphocytic leukemia by stopping blood flow to the tumor. 

PURPOSE: Phase II trial to study the effectiveness of thalidomide in treating patients who have relapsed chronic lymphocytic leukemia. 

Condition Treatment or Intervention Phase: refractory chronic lymphocytic leukemia - B-cell chronic lymphocytic leukemia 

Procedure: biological response modifier therapy 

Procedure: growth factor antagonist therapy 

Procedure: anti-cytokine therapy 

Procedure: antiangiogenesis therapy 

Drug: thalidomide Phase II 

MEDLINEplus related topics: Leukemia, Adult Acute; Leukemia, Adult Chronic; Leukemia, Childhood

Study Type: Treatment 

Official Title: Phase II Study of Thalidomide in Patients With Relapsed Chronic Lymphocytic Leukemia 

Further Study Details: 

OBJECTIVES: 

I. Determine the objective response in patients with relapsed chronic lymphocytic leukemia treated with thalidomide. 

II. Determine the toxicity of this drug in these patients.

III. Determine the correlation between vascular growth factors and/or bone marrow angiogenesis patterns and thalidomide-related clinical response in these patients.

PROTOCOL OUTLINE: Patients receive oral thalidomide daily for 4 weeks. Courses repeat every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 5 years.

PROJECTED ACCRUAL: A total of 12-41 patients will be accrued for this study within 28 months. 

Eligibility Ages - Eligible for Study: 18 Years and above Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics-- 

Diagnosis of chronic lymphocytic leukemia (CLL) evidenced by monoclonal population of mature CD5+, CD19+, CD23+ and B cells Relapsed after prior treatment for CLL Active disease with 1 or more of the following characteristics: At least 10% weight loss within the past 6 months Fever greater than 100.5 degrees F for at least 2 weeks without evidence of infection Night sweats without evidence of infection Evidence of progressive marrow failure with anemia (hemoglobin less than 11 g/dL) and/or thrombocytopenia (platelet count less than 100,000/mm3) (i.e., any stage III or IV disease) Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy Massive or progressive splenomegaly (i.e., greater than 6 cm below the left costal margin or more than 50% increase over 2 months) Massive or progressive lymphadenopathy (i.e., greater than 0 cm in longest diameter or more than 50% increase over 2 months) Progressive lymphocytosis (not due to corticosteroids) with an increase of more than 50% over a 2-month period or an anticipated doubling time of less than 6 months Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not considered evidence of active disease. Measurable disease Absolute lymphocyte count greater than 5,000/mm3. No bulky lymph node disease greater than 10 cm in at least 1 dimension except splenomegaly.

 --Prior/Concurrent Therapy--

Biologic therapy: No prior allogeneic bone marrow transplantation At least 10 days since prior filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy: No more than 3 prior chemotherapy regimens At least 30 days since prior chemotherapy 

Endocrine therapy: See Disease Characteristics No concurrent corticosteroids except for adrenal insufficiency.

Radiotherapy: Not specified 

Surgery: Not specified.

--Patient Characteristics--

Age: 18 and over

Performance status: ECOG 0-2

Life expectancy: Not specified

Hematopoietic: See Disease Characteristics Absolute neutrophil count at least 500/mm3 Platelet count at least 20,000/mm3 (in absence of GM-CSF)

Hepatic: Bilirubin no greater than 2.5 times upper limit of normal (ULN) AST no greater than 2.5 times ULN

Renal: Creatinine no greater than 1.5 mg/dL OR Creatinine clearance at least 60 mL/min

Other: No other active malignancy No peripheral neuropathy (sensory) grade 2 or greater No active infection Not pregnant or nursing Negative pregnancy test Fertile patients must use 1 highly effective method of contraception AND 1 additional effective method of contraception for at least 4 weeks before, during, and for 4 weeks after study. 

Location and Contact Information 

Saskatchewan, Canada. Allan Blair Cancer Centre, Regina, Saskatchewan, S4T 7T1, Canada; Recruiting Muhammad Salim 306-766-2203

Arizona CCOP - Scottsdale Oncology Program, Scottsdale, Arizona, 85259-5404, United States; Recruiting Tom Robert Fitch 480-301-8296

Illinois CCOP - Carle Cancer Center, Urbana, Illinois, 61801, United States; Recruiting Kendrith M. Rowland, Jr. 217-383-6846

Iowa CCOP - Cedar Rapids Oncology Project, Cedar Rapids, Iowa, 52403-1206, United States; Recruiting Martin Wiesenfeld 319-363-8303

Iowa CCOP - Iowa Oncology Research Association, Des Moines, Iowa, 50309-1016, United States; Recruiting Roscoe F. Morton 515-282-2921

Iowa Siouxland Hematology-Oncology, Sioux City, Iowa, 51101-1733, United States; Recruiting John C. Michalak 712-252-0088

Kansas CCOP - Wichita, Wichita, Kansas, 67214-3882, United States; Recruiting Shaker R. Dakhil 316-262-4467 

Minnesota CCOP - Duluth, Duluth, Minnesota, 55805, United States; Recruiting James Edward Krook 218-786-8364

Minnesota CCOP - Metro-Minnesota, Saint Louis Park, Minnesota, 55416, United States; Recruiting Patrick J. Flynn 612-863-8585

Minnesota CentraCare Clinic, Saint Cloud, Minnesota, 56303, United States; Recruiting Harold E. Windschitl 320-229-4907

Minnesota Mayo Clinic Cancer Center, Rochester, Minnesota, 55905, United States; Recruiting Neil E. Kay 507-284-2511

North Dakota CCOP - Merit Care Hospital, Fargo, North Dakota, 58122, United States; Recruiting Ralph Levitt 701-234-7592

North Dakota Medcenter One Health System, Bismarck, North Dakota, 58501, United States; Recruiting Ferdinand E. K. Addo 701-323-5365

Ohio CCOP - Toledo Community Hospital Oncology Program, Toledo, Ohio, 43623-3456, United States; Recruiting Paul L. Schaefer 419-479-5605

South Dakota CCOP - Sioux Community Cancer Consortium, Sioux Falls, South Dakota, 57104, United States; Recruiting Loren K. Tschetter 605-330-6510

South Dakota Rapid City Regional Hospital, Rapid City, South Dakota, 57709, United States; Recruiting Larry P. Ebbert 605-719-2301

Study chairs or principal investigators

Neil E. Kay, Study Chair

North Central Cancer Treatment Group

More Information

More information is available for this study.

Study ID Numbers 199/15350; NCCTG-N9986

Date study started September 15, 2000

Last Updated April 1, 2002

NLM Identifier NCT00006226

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Genasense Phase I/II Clinical Trial        

6/12/02

by Chaya Venkat

We have all heard about the antisense compound called Genasense from Genta corporation. It is now in phase -2 clinical trials at a number of hospitals around the country. Here is some of the clinical trial information, as well as contact information.

Announcement:

Phase I/II Study of Genasense in Patients With Chronic Lymphocytic Leukemia 

This study is currently recruiting patients.

Sponsored by Genta

Purpose: This non-randomized study will test the safety and effectiveness of Genasense in patients with CLL. 

Condition Treatment or InterventionPhase: Chronic Lymphocytic Leukemia

CLL Drug: Oblimerson, G3139 Phase I/Phase II

MEDLINEplus related topics: Leukemia, Adult Acute; Leukemia, Adult Chronic; Leukemia, Childhood

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Safety/Efficacy Study

Official Title: Phase I-II Multicenter Study of Genasense? (Bcl-2 Antisense Oligonucleotide) in Patients with Advanced Chronic Lymphocytic Leukemia

Further Study Details: This study is a two-part phase I-II study. Part 1 will determine the MTD of Genasense in patients with CLL. This dose will then be tested in a non-randomized, multi-center, Phase II sequential clinical trial of Genasense used alone for treatment of patients with advanced CLL. Pharmacokinetics of Genasense and kinetics of Bcl-2 down regulation and re-expression in CLL cells will be followed in selected patients.

Eligibility: Genders Eligible for Study: Both

Criteria: -Any age - Must have received at least one chemotherapy regimen that included fludarabine -Measurable disease -At least 3 weeks since biological therapy or radiation therapy for chronic lymphocytic leukemia -No previous stem cell transplantation -At least 3 weeks since surgery 

Expected Total Enrollment: 49

Location and Contact Information Patient Recruiter (888) 322-2264 

New York - Long Island Jewish Medical Center, New Hyde Park, New York, United States; Recruiting Patient Recruiter 888-322-2264 

Ohio - Ohio State University James Cancer Center, Columbus, Ohio, United States; Not yet recruiting Patient Recruiter 888-322-2264 

Texas - MD Anderson Cancer Center, Houston, Texas, United States; Recruiting Patient Recruiter 888-322-2264 

Texas - San Antonio Cancer Institute, San Antonio, Texas, United States; Recruiting Patient Recruiter 888-322-2264 

Texas - US Oncology, Dallas, Texas, United States; Recruiting  Patient Recruiter 888-322-2264 

More Information Genta's Website

Study ID Numbers GL208; G3139; Bcl-2 Antisense

Date study started January 2001

Record last reviewed January 2001

NLM Identifier NCT00021749 

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Genasense and Rituxan Combination - Phase II Clinical Trial for NHL

10/29/02

by Chaya Venkat

I had written earlier on murine (mouse) studies that showed a synergistic (more than additive) response when the monoclonal antibody Rituxan is combined with Genasense. Please see Combination Therapy with Genasense and Rituxan to read more about this subject. 

Now comes the announcement from the makers of the two drugs that they are about to start a Phase-I/II trial to study both safety and efficacy of this drug combination for NHL. It is interesting to remember, bcl-2, the target of Genasense, is highly expressed in many CLL patients. It is therefore reasonable to expect this combination, if it proves to be of value for NHL, will soon be tried for CLL patients as well. Next time one of you guys visits M. D. Anderson, why don't you try and find out more about this trial, when do they start recruiting, how many patients, what stage, naive or previously untreated, will they include SLL (code word for CLL) patients, etc. etc. You know the list.

Press Release: 

NCI INITIATES TRIAL OF GENASENSE™ PLUS RITUXAN® IN PATIENTS WITH NON-HODGKIN'S LYMPHOMA

BERKELEY HEIGHTS, NJ October 29, 2002 - Genta Incorporated (Nasdaq: GNTA), in collaboration with Aventis (NYSE:AVE), announced today the initiation of a new clinical trial that uses its lead anticancer drug, Genasense™, in combination with Rituxan® (rituximab; Genentech/IDEC), in patients with recurrent non-Hodgkin's lymphoma (NHL). This study, which is designed to evaluate safety and efficacy of the combination, will be led by the University of Texas M. D. Anderson Cancer Center in Houston with additional sites at Princess Margaret Hospital in Toronto and Fox Chase Cancer Center in Philadelphia. The trial will be sponsored by the U.S. National Cancer Institute, pursuant to Genta's Cooperative Research and Development Agreement (CRADA). Clinical studies published in both The Lancet and the Journal of Clinical Oncology have reported preliminary safety and efficacy results of Genasense™ when used alone in patients with advanced NHL. At the most recent meetings of the American Association of Cancer Research (AACR) and American Society of Hematology (ASH) investigators presented a number of preclinical studies demonstrating that Genasense™ strongly amplifies the anti-cancer activity of Rituxan®. In one such study, anticancer activity was seen when both Rituxan® and Genasense™ were used alone however, when used in combination a clear survival benefit was produced. "Rituxan is now widely considered a standard of care for the treatment of patients with NHL,"  commented Dr. Anas Younes, Associate Professor of Medicine, M. D. Anderson Cancer Center. "The strong preclinical data have supported the rapid translation of these findings into our clinical programs." "The Rituxan market seems to be growing at quite a fast pace. It is being used not only in NHL but front-line CLL and other lymphoid diseases. With the breath of Rituxan's use, and the substantial preclinical support for the Genasense/Rituxan combination, we made this a priority trial," commented Dr. Raymond P. Warrell, Chairman and Chief Executive Officer at Genta. 

Links to the referenced articles/abstracts: 

"Phase I Clinical and Pharmacokinetic Study of Bcl-2 Antisense Oligonucleotide Therapy in Patients With Non- Hodgkin's Lymphoma" JCO Vol 18 Issue 9 (May), 2000: 1812-1823 

"Bcl-2 Antisense Therapy in Patients with non-Hodgkin's Lymphoma" Lancet Ap19; 349 (9059):1137-41 

"Bcl-2 antisense (G3139, oblimerson) enhances the in vitro and in vivo response of EBV-associated lymphoproliferative disease to Rituximab." AACR 43; 2853, 2002. 

"Bcl-2 Antisense (GenasenseTM) Induces Apoptosis and Potentiates Activity of Both Cytotoxic Chemotherapy and Rituximab in Primary CLL Cells." ASH  3358, 2002

"Sequence Dependent Interaction of Bcl-2 Targeted Antisense Oligonucleotides (As-ODN) with Chemotherapy in Human DoHH2 Non-Hodgkin's Lymphoma (NHL) Cells."AACR 42; 3914, 2001. 

About Genasense 

Genasense™ works by inhibiting the production of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced cell death. By reducing the amount of Bcl-2 in cancer cells, Genasense™ may enhance the effectiveness of current anticancer treatments. Genasense™ is currently in multiple late-stage randomized clinical trials including malignant melanoma, multiple myeloma, chronic lymphocytic leukemia (CLL) and non-small cell lung cancer. 

About Rituxan 

Rituxan® (Rituximab) is a monoclonal antibody that binds to CD20, a molecule on the surface of lymphocytes. More than 90 percent of patients with B-cell NHL express CD20. Rituxan® is indicated for the treatment of patients with relapsed or refractory, low grade or follicular, CD20- positive, B-cell non-Hodgkin's lymphoma (NHL), which is cancer of the lymphatic system. It's a disease that's fatal in the large majority of patients. Approximately 55,000 patients are diagnosed annually with NHL in the United States.

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New Genasense Trial

8/1/03

by Chaya Venkat

A member has kindly sent me the information attached below on the latest Genasense clinical trial for CLL. 

Press Release:

Genta Initiates New Genasense(TM) Trial in Patients With Chronic Lymphocytic Leukemia

July 30, 2003 08:01:00 AM ET

Previously Untreated and Relapsed Patients to be Recruited for Combination Using Rituxan(R) Plus Fludarabine

BERKELEY HEIGHTS, N.J., July 30 /PRNewswire-FirstCall/ -- Genta Incorporated GNTA today announced the initiation of a new clinical trial with its lead anticancer drug, Genasense(TM) (oblimersen sodium), in patients with chronic lymphocytic leukemia (CLL). This Phase 2 study will evaluate the safety and efficacy of Genasense in combination with rituximab (Rituxan(R); Genentech/Idec) and fludarabine (Fludara(R); Berlex, Inc.). Although relapsed patients are eligible and will be separately analyzed, the trial represents the first use of Genasense in previously untreated patients with CLL using this new "standard-of-care" drug regimen. The study will be conducted at Roswell Park Cancer Institute, Buffalo, NY, Georgetown University's Lombardi Cancer Center, Baltimore, MD, and the Long Island Jewish University - Queens Medical Center, New York, NY. A randomized Phase 3 trial of Genasense in combination with fludarabine and cyclophosphamide completed enrollment earlier this year in patients with relapsed CLL. 

Genasense works by inhibiting the production of Bcl-2. This protein is highly expressed in CLL, where it is thought to block the initiation of chemotherapy-induced cell death. By reducing Bcl-2 in leukemia cells, Genasense may enhance the effectiveness of current anticancer treatments. Preclinical studies have shown that Genasense increases the antitumor activity of both fludarabine and rituximab in several types of cancer. In the new clinical trial, patients will receive up to 6 cycles of the Genasense/Rituxan/fludarabine combination. 

"We hope that by blocking Bcl-2 production, Genasense will enhance the response to both standard and novel cancer therapies," commented Dr. Loretta M. Itri, Genta's President, Pharmaceutical Development. "Our development program has tested Genasense in combination with a broad array of anticancer therapies in patients with many different hematologic cancers and solid tumors. In the U.S., the fludarabine/rituximab combination is rapidly becoming the new standard for previously untreated patients with CLL. This new trial complements our recently completed programs, and it positions Genasense to be the key enhancing agent in this disease." 

About CLL 

CLL is the most common form of leukemia in adults. Approximately 7,000 patients are expected to be diagnosed this year. The disease arises in lymphocytes, a type of white blood cell that normally produces antibodies and serves important immune functions. Patients with CLL typically develop symptoms that may progress over a period of years, ultimately producing a generalized depression of immunity, marked increases in the size of spleen, liver and lymph nodes, and impaired production other normal blood cells. Eventually, these problems may cause life-threatening complications, such as overwhelming infections and fatal bleeding. 

About Genasense 

Genasense inhibits production of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced cell death. By reducing the amount of Bcl-2 in cancer cells, Genasense may enhance the effectiveness of current anticancer treatments. Genasense is currently in multiple, late-stage, randomized clinical trials including malignant melanoma, multiple myeloma, chronic lymphocytic leukemia, and non-small cell lung cancer. 

About Genta

Genta Incorporated is a biopharmaceutical company with a diversified product portfolio that is focused on delivering innovative products for the treatment of patients with cancer. The Company's research platform is anchored by two programs that center on oligonucleotides (DNA/RNA-based medicines) and small molecules. Genasense(TM) (oblimersen sodium), the Company's lead compound from its oligonucleotide program, is being developed with Aventis and is currently undergoing late-stage, Phase 3 clinical testing. The leading drug in Genta's small molecule program is Ganite(TM) (gallium nitrate injection), which the Company expects to launch later this year for treatment of cancer-related hypercalcemia that is resistant to hydration. For more information about Genta, please visit our website at: www.genta.com. 

© 2003 PRNewswire

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Rituxan plus PT-100 Phase I Clinical Trial

8/17/03

by Chaya Venkat

We have discussed PT-100 as an exciting new drug, that may be particularly effective in combination with Rituxan. I have just heard that M. D. Anderson will be recruiting patients for this Phase I trial. I have obtained a full and detailed copy of the clinical trial protocol.

If you are interested, please use the form on our Feedback page or send an email to and we will be happy to send  you a copy of the Microsoft Word document.

A brief background description of how PT-100 works is given below, as well as links to two prior articles on the subject.

Here are a few highlights of the new trial:

Selection Criteria:

1. Patients must be confirmed CD20-positive, low-grade B- cell lymphoma or chronic lymphocytic leukemia (CLL) that is Chemotherapy-refractory, or has relapsed following a prior confirmed response to Rituxan. 

2. Platelets more than 50 x 109/L at baseline 

3. Patients with tumor masses less than 10cm 

3. No known resistance (absence of a CR or PR) to Rituxan therapy 

Phase - I protocol:

PT-100 administered orally in two divided doses every 12 hours on Study Days 1-6, 8-13, 15-20, and 22-27 

This is a dose escalation study, to evaluate toxicity of PT-100 in combination with Rituxan. So four groups of patients will be formed, with escalating amounts of PT-100, as below: 

* Cohort 1: 800µg/day (400µg, twice a day)
* Cohort 2: 1200µg/day (600µg twice a day)
* Cohort 3: 1800µg/day (900µg twice a day)
* Cohort 4: 2400µg/day (1200µg twice a day)

Rituxan will be given intravenously at the standard dose of 375 mg/m2, once a week for 4 weeks. (Study Days 0, 7, 14, 21) 

Patients are required to be in Houston, for the one month duration of this trial. It may also be necessary to return a few times for follow-up monitoring. Based on the results of this Phase - I trial, Anderson is contemplating a Phase - II trial. Also, while the Phase - I trial will recruit both NHL and CLL patients, the Phase - II trial will be split out into separate trials for NHL and CLL. It is expected that the Phase -II trial will be double-blind, placebo controlled and multi-center trial. Placebo controlled means that half of the patients will get Rituxan plus PT-100, and the other half will get Rituxan plus a dummy pill. The study will be "blind", in that no one will know who got the PT-100 and who got the dummy pill until the results are in. This is standard procedure for all well controlled clinical trials, so as to avoid biasing the results. 

I don't know about you guys, but finding out about this trial made my day. More power to M. D. Anderson! In the next few days I will also be writing about the details of the Rituxan plus GM-CSF clinical trial. It now seems this trial will not, repeat, NOT be restricted to patients over 70, as I originally reported. These are two good, solid clinical trials using practical and feasible technology that is available here and now. And not too soon! They both have the benefit of making Rituxan therapy more attractive to CLL patients. 

When P.C. is ready for his second go-around, you can bet we will be taking a very good hard look at these two options.

Background on PT-100:

The company (Point Therapeutics) claims that PT-100 has the ability to stimulate the growth of primitive hematopoietic progenitor cells. They believe that PT-100 interacts with stromal cells to increase the production of certain hematopoietic growth factors, required for the development and differentiation of mature blood cells. For example, PT-100 is expected to stimulate the production of the growth factor G-CSF, which is a protein involved in both the expansion of primitive hematopoietic progenitor cells and the differentiation of committed progenitor cells into neutrophils. 

In mouse studies, Point Therapeutics demonstrated that PT-100 significantly accelerated neutrophil recovery in mice following chemotherapy. They have also tested PT-100 in an animal model of acute anemia. Results of these tests demonstrated that mice pretreated with PT-100 developed less severe anemia due to significantly faster recovery of mature red blood cells than in the control animals. In addition, committed progenitors of red blood cells were substantially increased in PT-100-treated mice, which supports previous observations that PT-100 increases the primitive hematopoietic progenitor pool in the bone marrow of mice.

I also tracked down an ASCO 2003 abstract that describes oral treatment of tumors in mice. They showed significant anti-tumor effect attributed to increased CTL (cytotoxic T-cells) activity, increased production of neutrophils and NK-cells and macrophages, all of which are involved in attacking tumor cells. These are all the cell types we have discussed many times before as the necessary part of Rituxan therapy. They are the cells that do the actual killing of cancer cells tagged by Rituxan. The abstract goes on to claim that in animal studies, combination of Rituxan plus PT-100 had increased effectiveness. This is the work that is the basis of the newly announced clinical trial for CLL patients, combining Rituxan with PT-100. 

This is not explicitly stated on the company website, but my guess would be that increased levels of CSFs (Colony Stimulating Factors) may also up-regulate expression of CD20. That is one of the reasons why GM-CSF is being tried in clinical trials with Rituxan. Since PT-100 up-regulates CSF production, perhaps it is reasonable to assume the next happens as well, the CSF in turn up-regulates CD20 expression. That would be of special interest to CLL patients, since we typically have lower antigen density (lower expression of CD20 both as percentage of cells expressing it, as well as intensity). 

CLL Topics Link:

PT-100 plus Rituxan Therapy

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Pentostatin + Cyclophosphamide + Rituxan Trial at Mayo Clinic

1/2/04

by Chaya Venkat

The following protocol is derived from a poster session at the 2003 ASH meeting in San Diego.

Pentostatin Combination Therapy for Untreated B-Chronic Lymphocytic Leukemia. Session Type: Poster Session 675-II

Neil E. Kay, Thomas Lin, Timothy Call, Diane F. Jelinek, Nancy D. Bone, Gordon W. Dewald, Nyla A. Heerema, Renee Tschumper, Lisa Smith, Susan M. Geyer, John C. Byrd

Division of Hematology, Mayo Clinic, Rochester, MN, USA; Division of Hematology Oncology, Ohio State University, Columbus, OH, USA; Deptment of Immunology, Mayo Clinic, Rochester, MN, USA; Department of Pathology, Ohio State University, Columbus, OH, USA

The nucleoside analogue Pentostatin has clinical activity in B-Cell Chronic Lymphocytic Leukemia (CLL) and has shown significant activity and minimal toxicity when combined with cyclophosphamide (Weiss M, JCO, 2003). To build on this promising intervention, we initiated a trial of combined pentostatin (2mg/M2), cyclophosphamide (600 mg/M2) and rituximab (375 mg/M2) for initial therapy of previously untreated B-CLL. This P(pentostatin) C(cyclophosphamide) R(Rituxan) regimen is given on a 21-day, 6-cycle schedule. However, the initial cycle of treatment uses thrice weekly Rituximab as described by us earlier (Byrd J, JCO, 2001). In this trial 33 patients have now been enrolled. An interim analysis was performed on the first 15: 12 males, 3 females; median age 56 (range 44-79); Rai stage 0 (N=1), 1 (N=4), 2 (N=3), 3 (N=3) and 4 (N=4). The objective response was evaluated using the NCI 96 working group criteria. All 15 patients (100%) had a best response of a partial response or better. Including review of bone marrows done 2 months post-treatment, there are 6 CRs (complete response), 2 CCRs (clinical complete response), and 7 partial responses (PR). In follow-up of patients post- herapy, we utilize both two (CD5+/CD19+) and three-color (CD5+/CD19+/CD79b-) flow cytometry of blood lymphocytes. This analysis has revealed no detectable disease in 2 and from <1 to 5% clonal cells in 11. Clinical responses occurred rapidly with a median time to response (PR or CCR) of 48 days, and median time to absolute lymphocyte count (ALC) normalization of 45 days. The toxicity profile revealed that no patients required red cell or platelet transfusions during treatment. While most toxicities were grade 1-2, there were 8 grade 3 (anemia, hypotension) and 1 grade 4 (sinus bradycardia). Each patient had a CLL FISH panel that studies common recurring genetic defects in B-CLL (i.e. +12, 13q-, 11q-, 6q- and 17p-) done at entry to the study. FISH defects were found in 11 of 15 including several with high-risk genetic defects (i.e., 6q-, 11q-, 17p-). Consistent with the normalization of ALC, 5 patients with FISH defects had no detectable FISH defects within a median of 183 days. Median follow-up on the first 15 patients is 258 days (range: 144-452), where all 33 patients continue to be followed. To date 2 of the 15 patients have evidence of progression at 172 and 200 days, respectively. In conclusion, this novel regimen of pentostatin, cyclophosphamide and rituximab demonstrates significant clinical activity with rapid induction of responses, achievement of minimal residual disease in some, and tolerable toxicity. Chronic Lymphocytic Leukemia Consortium Members and this work is supported by an NCI R01(CA95241)

Abstract #2504 appears in Blood, Volume 102, issue 11, November 16, 2003

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